Prostate cancer

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 Laura S. Graham, MD
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 Ali Raza Khaki, MD
Stanford University
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: this page contains regimens for prostate cancer which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages:

78 regimens on this page
107 variants on this page


Living Interactive Systematic Reviews

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

ASCO & CCO

AUA

ASTRO/ASCO/AUA

EAU/ESTRO/SIOG

ESMO

NCCN

SIOG

SITC

St Gallen

Induction ADT

ADT

ADT: Androgen Deprivation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Roach et al. 2003 (RTOG 94-13) 1995-1999 Phase 3 (E-switch-ic) ADT; adjuvant Did not meet primary endpoint of PFS
Pisansky et al. 2014 (RTOG 9910) 2000-2004 Phase 3 (C) ADT x 28 weeks Did not meet primary endpoint of disease-specific mortality

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Endocrine therapy

8-week course

Subsequent treatment

References

  1. RTOG 94-13: Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay M, Seider MJ, Rotman M, Jones C, Asbell SO, Valicenti RK, Hahn S, Thomas CR Jr, Shipley WS; Radiation Therapy Oncology Group. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003 May 15;21(10):1904-11. link to original article PubMed NCT00769548
    1. Update: Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, Rotman M, Jones C, Asbell S, Valicenti R, Hahn S, Thomas CR Jr. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55. Epub 2007 May 24. link to original article link to PMC article PubMed
  2. RTOG 9910: Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. link to original article link to PMC article PubMed NCT00005044

Bicalutamide & Goserelin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mason et al. 2012 (FE200486 CS30) 2009-NR Phase 3 (C) Degarelix Non-inferior total prostate volume reduction at week 12

Endocrine therapy

12-week course

Subsequent treatment

  • Definitive RT

References

  1. FE200486 CS30: Mason M, Maldonado Pijoan X, Steidle C, Guerif S, Wiegel T, van der Meulen E, Bergqvist PB, Khoo V. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide. Clin Oncol (R Coll Radiol). 2013 Mar;25(3):190-6. Epub 2012 Dec 17. link to original article contains dosing details in manuscript PubMed NCT00833248

Degarelix monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mason et al. 2012 (FE200486 CS30) 2009-NR Phase 3 (E-switch-ic) Bicalutamide & Goserelin Non-inferior total prostate volume reduction at week 12 (primary endpoint)

Endocrine therapy

12-week course

Subsequent treatment

  • Definitive RT

References

  1. FE200486 CS30: Mason M, Maldonado Pijoan X, Steidle C, Guerif S, Wiegel T, van der Meulen E, Bergqvist PB, Khoo V. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide. Clin Oncol (R Coll Radiol). 2013 Mar;25(3):190-6. Epub 2012 Dec 17. link to original article contains dosing details in manuscript PubMed NCT00833248

Flutamide & Goserelin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Crook et al. 2004 1995-2001 Phase 3 (C) Flutamide & Goserelin x 8 mo Did not meet primary endpoint of PSA-PFS

Endocrine therapy

3-month course

Subsequent treatment

  • Definitive RT

References

  1. Crook J, Ludgate C, Malone S, Lim J, Perry G, Eapen L, Bowen J, Robertson S, Lockwood G. Report of a multicenter Canadian phase III randomized trial of 3 months vs 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):15-23. link to original article PubMed
    1. Update: Crook J, Ludgate C, Malone S, Perry G, Eapen L, Bowen J, Robertson S, Lockwood G. Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):327-33. Epub 2008 Aug 15. link to original article PubMed

Leuprolide monotherapy

Regimen

Study Dates of enrollment Evidence
Denham et al. 2014 (RADAR) 2003-2007 Non-randomized part of phase 3 RCT

Note: this trial had 4 arms including a randomization to zoledronic acid; see paper for details.

Endocrine therapy

3-month cycle for 2 cycles

Subsequent treatment

References

  1. RADAR: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial. Lancet Oncol. 2014 Sep;15(10):1076-89. Epub 2014 Aug 14. link to original article PubMed NCT00193856
    1. Update: Denham JW, Joseph D, Lamb DS, Spry NA, Duchesne G, Matthews J, Atkinson C, Tai KH, Christie D, Kenny L, Turner S, Gogna NK, Diamond T, Delahunt B, Oldmeadow C, Attia J, Steigler A. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019 Feb;20(2):267-281. Epub 2018 Dec 19. link to original article PubMed

Definitive therapy, including active surveillance

Active surveillance

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Holmberg et al. 2002 (SPCG-4) 1989-1999 Phase 3 (C) Radical prostatectomy Inferior OS1
Wilt et al. 2012 (PIVOT) 1994-2002 Phase 3 (C) Radical prostatectomy Did not meet primary endpoint of OS
Hamdy et al. 2016 (ProtecT) 1999-2009 Phase 3 (C) 1. Prostatectomy
2. RT 		Did not meet primary endpoint of OS
Fleshner et al. 2012 (REDEEM) 2006-08-10 to 2007-03-26 Phase 3 (C) Dutasteride Inferior TTP
Azzouzi et al. 2016 (CLIN1001 PCM301) 2011-2013 Phase 3 (C) Padeliporfin Inferior TTP

1Reported efficacy for SPCG-4 is based on the 2018 update.
No antineoplastic therapy; consists of various strategies of close monitoring and re-biopsy.

References

  1. SPCG-4: Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Häggman M, Andersson SO, Spångberg A, Busch C, Nordling S, Palmgren J, Adami HO, Johansson JE, Norlén BJ; Scandinavian Prostatic Cancer Group. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med. 2002 Sep 12;347(11):781-9. link to original article PubMed
    1. Update: Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005 May 12;352(19):1977-84. link to original article PubMed
    2. Update: Bill-Axelson A, Holmberg L, Filén F, Ruutu M, Garmo H, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Adami HO, Johansson JE; Scandinavian Prostate Cancer Group. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008 Aug 20;100(16):1144-54. Epub 2008 Aug 11. link to original article link to PMC article PubMed
    3. Update: Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami HO, Johansson JE; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011 May 5;364(18):1708-17. link to original article PubMed
    4. Update: Bill-Axelson A, Holmberg L, Garmo H, Rider JR, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Spångberg A, Andrén O, Palmgren J, Steineck G, Adami HO, Johansson JE. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014 Mar 6;370(10):932-42. link to original article link to PMC article PubMed
    5. Update: Bill-Axelson A, Holmberg L, Garmo H, Taari K, Busch C, Nordling S, Häggman M, Andersson SO, Andrén O, Steineck G, Adami HO, Johansson JE. Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up. N Engl J Med. 2018 Dec 13;379(24):2319-2329. link to original article PubMed
  2. REDEEM: Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, Black L, Rittmaster RS. Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. Lancet. 2012 Mar 24;379(9821):1103-11. Epub 2012 Jan 24. link to original article PubMed NCT00363311
  3. PIVOT: Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Sharifi R, Blank W, Pandya P, Andriole GL, Culkin D, Wheeler T; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012 Jul 19;367(3):203-13. Erratum in: N Engl J Med. 2012 Aug 9;367(6):582. link to original article link to PMC article PubMed NCT00007644
    1. Update: Wilt TJ, Jones KM, Barry MJ, Andriole GL, Culkin D, Wheeler T, Aronson WJ, Brawer MK. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med. 2017 Jul 13;377(2):132-142. link to original article PubMed
  4. ProtecT: Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, Davis M, Peters TJ, Turner EL, Martin RM, Oxley J, Robinson M, Staffurth J, Walsh E, Bollina P, Catto J, Doble A, Doherty A, Gillatt D, Kockelbergh R, Kynaston H, Paul A, Powell P, Prescott S, Rosario DJ, Rowe E, Neal DE; ProtecT Study Group. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med. 2016 Oct 13;375(15):1415-1424. Epub 2016 Sep 14. link to original article PubMed NCT02044172
    1. Update: Hamdy FC, Donovan JL, Lane JA, Metcalfe C, Davis M, Turner EL, Martin RM, Young GJ, Walsh EI, Bryant RJ, Bollina P, Doble A, Doherty A, Gillatt D, Gnanapragasam V, Hughes O, Kockelbergh R, Kynaston H, Paul A, Paez E, Powell P, Rosario DJ, Rowe E, Mason M, Catto JWF, Peters TJ, Oxley J, Williams NJ, Staffurth J, Neal DE; ProtecT Study Group. Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med. 2023 Apr 27;388(17):1547-1558. Epub 2023 Mar 11. link to original article PubMed
  5. CLIN1001 PCM301: Azzouzi AR, Vincendeau S, Barret E, Cicco A, Kleinclauss F, van der Poel HG, Stief CG, Rassweiler J, Salomon G, Solsona E, Alcaraz A, Tammela TT, Rosario DJ, Gomez-Veiga F, Ahlgren G, Benzaghou F, Gaillac B, Amzal B, Debruyne FM, Fromont G, Gratzke C, Emberton M; PCM301 Study Group. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191. Epub 2016 Dec 20. link to original article PubMed NCT01310894

ADT

ADT: Androgen Deprivation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07) 1995-2005 Phase 3 (C) ADT & RT Seems to have inferior OS

Note: these are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.

Endocrine therapy

References

  1. NCIC-CTG PR.3/UK MRC PR07: Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC-CTG; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. link to original article link to PMC article PubMed NCT00002633

ADT & RT

ADT & RT: Androgen Deprivation Therapy & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
d'Amico et al. 2004 1995-2001 Phase 3 (E-esc) RT Seems to have superior OS (co-primary endpoint)
OS60: 88% vs 78%
(HR 0.48, 95% CI 0.24-0.98)
Warde et al. 2011 (NCIC-CTG PR.3/UK MRC PR07) 1995-2005 Phase 3 (E-esc) ADT Seems to have superior OS (primary endpoint)
OS84: 74% vs 66%
(HR 0.77, 95% CI 0.61-0.98)
Bolla et al. 2009 (EORTC 22961) 1997-2001 Non-randomized part of phase 3 RCT
Rosenthal et al. 2008 (RTOG 9902) 2000-2004 Non-randomized part of phase 3 RCT
Pisansky et al. 2014 (RTOG 9910) 2000-2004 Non-randomized part of phase 3 RCT
Nabid et al. 2018 (PCS IV) 2000-2008 Non-randomized part of phase 3 RCT
Nabid et al. 2020 (PCS III) 2000-2010 Phase 3 (E-esc) 1. RT Superior biochemical failure (primary endpoint)
2. ADT & RT; dose-escalated RT Did not meet primary endpoint of biochemical failure
Ito et al. 2020 2001-2006 Non-randomized part of phase 3 RCT
Bolla et al. 2016 (EORTC 22991) 2001-2008 Phase 3 (E-esc) RT Superior PFS (secondary endpoint)
DFS60: 88.7% vs 80.8%
(HR 0.63, 95% CI 0.48-0.84)
Malone et al. 2019 2002-2012 Non-randomized part of phase 3 RCT
Zapatero et al. 2015 (DART01/05 GICOR) 2005-2010 Non-randomized part of phase 3 RCT
D'Amico et al. 2021 (DFCI 05-043) 2005-2015 Phase 3 (C) ADT, Docetaxel, RT Did not meet primary endpoint of OS
Yorozu et al. 2023 (TRIP) 2010-10 to 2013-03 Non-randomized part of phase 3 RCT

Note: these were clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details; we will work on improving this section soon.

Preceding treatment

  • RTOG 9902 & DART01/05 GICOR: Induction ADT x 8 weeks
  • RTOG 9910: Induction ADT x 8 weeks versus ADT x 28 weeks

Endocrine therapy

Radiotherapy

8-week course

Subsequent treatment

  • RTOG 9902: Adjuvant ADT x 2 y versus TEE x 4, then ADT x 2 y
  • EORTC 22961: Adjuvant ADT x 6 months versus ADT x 36 months
  • DART01/05 GICOR: Adjuvant ADT x 24 months versus no further treatment
  • PCS IV: Adjuvant ADT x 18 months versus ADT x 36 months

References

  1. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):821-7. link to original article PubMed
  2. RTOG 9902: Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM; Radiation Therapy Oncology Group. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. Epub 2008 Nov 5. link to original article PubMed NCT00004054
    1. Update: Rosenthal SA, Hunt D, Sartor AO, Pienta KJ, Gomella L, Grignon D, Rajan R, Kerlin KJ, Jones CU, Dobelbower M, Shipley WU, Zeitzer K, Hamstra DA, Donavanik V, Rotman M, Hartford AC, Michalski J, Seider M, Kim H, Kuban DA, Moughan J, Sandler H. A phase 3 trial of 2 years of androgen suppression and radiation therapy with or without adjuvant chemotherapy for high-risk prostate cancer: final results of radiation therapy oncology group phase 3 randomized trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys. 2015 Oct 1;93(2):294-302. Epub 2015 Jul 21. link to original article link to PMC article PubMed
  3. EORTC 22961: Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G, Kariakine O, van der Steen-Banasik EM, Musat E, Piérart M, Mauer ME, Collette L; EORTC Radiation Oncology Group; EORTC Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009 Jun 11;360(24):2516-27. link to original article PubMed NCT00003026
  4. NCIC-CTG PR.3/UK MRC PR07: Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC; MRC. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. Epub 2011 Nov 2. link to original article link to PMC article PubMed NCT00002633
  5. RTOG 9910: Pisansky TM, Hunt D, Gomella LG, Amin MB, Balogh AG, Chinn DM, Seider MJ, Duclos M, Rosenthal SA, Bauman GS, Gore EM, Rotman MZ, Lukka HR, Shipley WU, Dignam JJ, Sandler HM. Duration of androgen suppression before radiotherapy for localized prostate cancer: Radiation Therapy Oncology Group randomized clinical trial 9910. J Clin Oncol. 2015 Feb 1;33(4):332-9. Epub 2014 Dec 22. link to original article link to PMC article PubMed NCT00005044
  6. DART01/05 GICOR: Zapatero A, Guerrero A, Maldonado X, Alvarez A, Gonzalez San Segundo C, Cabeza Rodríguez MA, Macias V, Pedro Olive A, Casas F, Boladeras A, de Vidales CM, Vazquez de la Torre ML, Villà S, Perez de la Haza A, Calvo FA. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Mar;16(3):320-7. Epub 2015 Feb 19. Erratum in: Lancet Oncol. 2015 Jun;16(6):e262. link to original article PubMed NCT02175212
  7. EORTC 22991: Bolla M, Maingon P, Carrie C, Villa S, Kitsios P, Poortmans PM, Sundar S, van der Steen-Banasik EM, Armstrong J, Bosset JF, Herrera FG, Pieters B, Slot A, Bahl A, Ben-Yosef R, Boehmer D, Scrase C, Renard L, Shash E, Coens C, van den Bergh AC, Collette L. Short androgen suppression and radiation dose escalation for intermediate- and high-risk localized prostate cancer: results of EORTC trial 22991. J Clin Oncol. 2016 May 20;34(15):1748-56. Epub 2016 Mar 14. link to original article PubMed NCT00021450
    1. Subgroup analysis: Bolla M, Neven A, Maingon P, Carrie C, Boladeras A, Andreopoulos D, Engelen A, Sundar S, van der Steen-Banasik EM, Armstrong J, Peignaux-Casasnovas K, Boustani J, Herrera FG, Pieters BR, Slot A, Bahl A, Scrase CD, Azria D, Jansa J, O'Sullivan JM, Van Den Bergh ACM, Collette L; EORTC Radiation Oncology Group. Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease. J Clin Oncol. 2021 Sep 20;39(27):3022-3033. Epub 2021 Jul 26. link to original article PubMed
  8. PCS IV: Nabid A, Carrier N, Martin AG, Bahary JP, Lemaire C, Vass S, Bahoric B, Archambault R, Vincent F, Bettahar R, Duclos M, Garant MP, Souhami L. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018 Oct;74(4):432-441. Epub 2018 Jul 3. link to original article PubMed NCT00223171
  9. Malone S, Roy S, Eapen L, E C, MacRae R, Perry G, Bowen J, Samant R, Morgan S, Craig J, Malone K, Grimes S. Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial. J Clin Oncol. 2020 Feb 20;38(6):593-601. Epub 2019 Dec 12. Erratum in: J Clin Oncol. 2020 Jun 10;38(17):2005. link to original article link to PMC article PubMed
  10. Ito K, Kobayashi M, Komiyama M, Naito S, Nishimura K, Yonese J, Hashine K, Saito S, Arai G, Shinohara M, Masumori N, Shimizu N, Satoh T, Yamauchi A, Tochigi T, Takezawa Y, Fujimoto H, Yokomizo A, Kakimoto KI, Fukui I, Karasawa K, Tsukamoto T, Nozaki M, Hasumi M, Ishiyama H, Ohtani M, Kuwahara M, Harada M, Ohashi Y, Kotake T, Kakizoe T, Suzuki K, Yamanaka H; National Research Project on Endocrine-Radiation Combination Therapy for Locally Advanced Prostate Cancer Investigators. Oncological outcomes for patients with locally advanced prostate cancer treated with neoadjuvant endocrine and external-beam radiation therapy followed by adjuvant continuous/intermittent endocrine therapy in an open-label, randomized, phase 3 trial. Cancer. 2020 Sep 1;126(17):3961-3971. Epub 2020 Jun 23. link to original article PubMed
  11. PCS III: Nabid A, Carrier N, Vigneault E, Van Nguyen T, Vavassis P, Brassard MA, Bahoric B, Archambault R, Vincent F, Bettahar R, Wilke D, Souhami L. Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial. Eur J Cancer. 2021 Jan;143:64-74. Epub 2020 Dec 3. link to original article PubMed NCT00223145
  12. DFCI 05-043: D'Amico AV, Xie W, McMahon E, Loffredo M, Medeiros S, Joseph D, Denham J, Kumar P, Bubley G, Sullivan M, Hellwig R, Carlos Vera J, Freter R, Jeffrey Baker W, Wong JY, Renshaw AA, Kantoff PW. Radiation and Androgen Deprivation Therapy With or Without Docetaxel in the Management of Nonmetastatic Unfavorable-Risk Prostate Cancer: A Prospective Randomized Trial. J Clin Oncol. 2021 Sep 10;39(26):2938-2947. Epub 2021 Jul 1. link to original article link to PMC article PubMed NCT00116142
  13. TRIP: Yorozu A, Namiki M, Saito S, Egawa S, Yaegashi H, Konaka H, Momma T, Fukagai T, Tanaka N, Ohashi T, Takahashi H, Nakagawa Y, Kikuchi T, Mizokami A, Stone NN. Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907). Int J Radiat Oncol Biol Phys. 2024 Feb 1;118(2):390-401. Epub 2023 Oct 4. link to original article PubMed UMIN000003992

Flutamide, Goserelin, RT

Flutamide, Goserelin, RT: Flutamide, Goserelin, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pilepich et al. 1995 1987-1991 Phase 3 (E-RT-esc) RT Superior DFS
Pilepich et al. 2001 (RTOG 86-10) 1987-1991 Phase 3 (E-esc) RT Seems to have superior cause-specific mortality
Hanks et al. 2003 (RTOG 92-02) 1992-1995 Non-randomized part of phase 3 RCT
Jones et al. 2011 (RTOG 94-08) 1994-2001 Phase 3 (E-esc) RT Seems to have superior OS (primary endpoint)
OS120: 62% vs 57%
(HR 0.85, 95% CI 0.74-0.99)
D'Amico et al. 2008 (DFCI 95-096) 1995-2001 Randomized (E-esc) RT Superior OS (primary endpoint)
OS96: 74% vs 61%
(HR 0.56, 95% CI 0.34-0.91)
Denham et al. 2005 (TROG 96.01) 1996-2000 Phase 3 (E-esc) 1. Flutamide, Goserelin, RT; 6 months of ADT Not reported
2. RT Superior EFS (secondary endpoint)

Endocrine therapy

28-day cycles, starting 2 months prior to radiation therapy and continuing at least through the end of radiation therapy

Radiotherapy

  • External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 200 cGy per fraction, with an initial 44 to 4600 cGy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 7000 cGy

7-week course

Subsequent treatment

References

  1. Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, Lawton CA, Abrams RA, Rotman M, Rubin P, Shipley WU, Grignon D, Caplan R, Cox JD; Radiation Therapy Oncology Group. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology. 1995 Apr;45(4):616-23. link to original article PubMed
  2. RTOG 86-10: Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, Lawton C, Machtay M, Grignon D. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52. link to original article contains dosing details in manuscript PubMed
    1. Update: Roach M 3rd, Bae K, Speight J, Wolkov HB, Rubin P, Lee RJ, Lawton C, Valicenti R, Grignon D, Pilepich MV. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol. 2008 Feb 1;26(4):585-91. Epub 2008 Jan 2. link to original article contains dosing details in manuscript PubMed
  3. RTOG 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. link to original article contains dosing details in abstract PubMed
    1. Update: Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. link to original article contains dosing details in manuscript PubMed
    2. Update: Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. link to original article link to PMC article PubMed
  4. TROG 96.01: Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, Turner S, Matthews J, Franklin I, Atkinson C, North J, Poulsen M, Christie D, Spry NA, Tai KH, Wynne C, Duchesne G, Kovacev O, D'Este C; Trans-Tasman Radiation Oncology Group. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol. 2005 Nov;6(11):841-50. link to original article contains dosing details in abstract PubMed ACTRN12607000237482
    1. Update: Denham JW, Steigler A, Lamb DS, Joseph D, Turner S, Matthews J, Atkinson C, North J, Christie D, Spry NA, Tai KH, Wynne C, D'Este C. Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol. 2011 May;12(5):451-9. link to original article PubMed
  5. DFCI 95-096: D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008 Jan 23;299(3):289-95. link to original article PubMed content property of HemOnc.org NCT00116220
    1. Update: D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA. 2015 Sep 22-29;314(12):1291-3. link to original article PubMed
  6. RTOG 94-08: Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. link to original article contains dosing details in manuscript PubMed NCT00002597

Flutamide, Leuprolide, RT

Flutamide, Leuprolide, RT: Flutamide, Leuprolide, Radiation Therapy

Regimen variant #1, 4 months of ADT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jones et al. 2011 (RTOG 94-08) 1994-2001 Phase 3 (E-esc) RT Seems to have superior OS (primary endpoint)
OS120: 62% vs 57%
(HR 0.85, 95% CI 0.74-0.99)

Endocrine therapy

28-day cycle for 4 cycles

Radiotherapy

  • External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 200 cGy per fraction, with an initial 44 to 4600 cGy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 7000 cGy


Regimen variant #2, 3 years of ADT

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mottet et al. 2012 (TAP 32) 2000-2003 Phase 3 (E-esc) Flutamide & Leuprolide Superior PFS60 (primary endpoint)

Endocrine therapy

3-month cycle for 12 cycles (3 years)

Radiotherapy

One course


Regimen variant #3, indefinite ADT, monthly leuprolide

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Widmark et al. 2008 (SPCG-7/SFUO-3) 1996-2002 Phase 3 (C) Flutamide & Leuprolide Superior OS

Endocrine therapy

  • Flutamide (Eulexin) 250 mg PO three times per day on days 1 to 28, starting 3 months prior to radiation therapy
  • Leuprolide (Lupron) as follows, starting 3 months prior to radiation therapy:
    • Cycles 1 to 3: 3.75 mg SC once on day 1

28-day cycles

Radiotherapy


Regimen variant #4, indefinite ADT, 3-monthly leuprolide

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Widmark et al. 2008 (SPCG-7/SFUO-3) 1996-2002 Phase 3 (C) Flutamide & Leuprolide Superior OS

Endocrine therapy

  • Flutamide (Eulexin) 250 mg PO three times per day on days 1 to 28, starting 3 months prior to radiation therapy
  • Leuprolide (Lupron) as follows, starting 3 months prior to radiation therapy:
    • Cycle 1: 11.25 mg SC once on day 1

28-day cycles

Radiotherapy

References

  1. SPCG-7/SFUO-3: Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fosså SD; Scandinavian Prostate Cancer Group; Swedish Association for Urological Oncology. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8. Epub 2008 Dec 16. Erratum in: Lancet. 2009 Apr 4;373(9670):1174. link to original article contains dosing details in manuscript PubMed ISRCTN01534787
  2. RTOG 94-08: Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, Rotman M, Souhami L, Sandler HM, Shipley WU. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011 Jul 14;365(2):107-18. link to original article contains dosing details in manuscript PubMed NCT00002597
  3. TAP 32: Mottet N, Peneau M, Mazeron JJ, Molinie V, Richaud P. Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial. Eur Urol. 2012 Aug;62(2):213-9. Epub 2012 Apr 3. link to original article PubMed NCT01122121
    1. Update: Sargos P, Mottet N, Bellera C, Richaud P. Long-term androgen deprivation, with or without radiotherapy, in locally advanced prostate cancer: updated results from a phase III randomised trial. BJU Int. 2020 Jun;125(6):810-816. Epub 2020 Mar 2. link to original article contains dosing details in manuscript PubMed

Goserelin & RT

Goserelin & RT: Goserelin & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pilepich et al. 2005 (RTOG 85-31) 1987-1992 Phase 3 (E-esc) RT Superior DFS
Bolla et al. 1997 (EORTC 22863) 1987-1995 Phase 3 (E-esc) RT Superior OS

Endocrine therapy

28-day cycles

Radiotherapy

  • External beam radiotherapy, 1.8 to 200 cGy per fraction, with an initial 44 to 4600 cGy to the pelvis, then an additional boost to the prostate that resulted in a total dose of 65 to 7000 cGy in definitive radiation patients; 60 to 6500 cGy total dose for post-prostatectomy patients

One course

References

  1. RTOG 85-31: Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, Hanks GE, Coughlin CT, Porter A, Shipley WU, Grignon D. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol. 1997 Mar;15(3):1013-21. link to original article contains dosing details in abstract PubMed
    1. Update: Lawton CA, Winter K, Murray K, Machtay M, Mesic JB, Hanks GE, Coughlin CT, Pilepich MV. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):937-46. link to original article contains dosing details in abstract PubMed
    2. Update: Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, Hug EB, Asbell SO, Grignon D. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90. link to original article contains dosing details in manuscript PubMed
  2. EORTC 22863: Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997 Jul 31;337(5):295-300. link to original article PubMed NCT00849082
    1. Update: Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez Torecilla J, Pfeffer JR, Lino Cutajar C, Zurlo A, Pierart M. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6. link to original article PubMed
    2. Update: Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Billiet I, Torecilla JL, Pfeffer R, Cutajar CL, Van der Kwast T, Collette L. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010 Nov;11(11):1066-73. Epub 2010 Oct 7. link to original article PubMed

Adjuvant therapy

Bicalutamide & Goserelin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dorff et al. 2011 (SWOG S9921) 2000-2007 Phase 3 (C) ADT & Mitoxantrone Did not meet primary endpoint of OS1

1Reported efficacy is based on the 2018 update.
Dosing details are not available in the manuscript; this is the common dosing used.

Preceding treatment

Endocrine therapy

12-week cycle for 9 cycles (2 years)

References

  1. SWOG S9921: Dorff TB, Flaig TW, Tangen CM, Hussain MH, Swanson GP, Wood DP Jr, Sakr WA, Dawson NA, Haas NB, Crawford ED, Vogelzang NJ, Thompson IM, Glode LM. Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011 May 20;29(15):2040-5. Epub 2011 Apr 18. link to original article does not contain dosing details link to PMC article PubMed NCT00004124
    1. Update: Hussain M, Tangen CM, Thompson IM Jr, Swanson GP, Wood DP, Sakr W, Dawson NA, Haas NB, Flaig TW, Dorff TB, Lin DW, Crawford ED, Quinn DI, Vogelzang NJ, Glode LM. Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921. J Clin Oncol. 2018 May 20;36(15):1498-1504. Epub 2018 Apr 6. Erratum in: J Clin Oncol. 2018 Jul 10;36(20):2131. link to original article link to PMC article PubMed

Goserelin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Messing et al. 1999 (ECOG E3886) 1988-1993 Phase 3 (E-esc) No further treatment Seems to have superior OS
Hanks et al. 2003 (RTOG 92-02) 1992-1995 Phase 3 (E-esc) No further treatment Seems to have superior OS1

1Reported efficacy of RTOG 92-02 based on the 2017 update.

Preceding treatment

Endocrine therapy

2-year course (RTOG 92-02) or until rising PSA detected (ECOG E3886)

References

  1. ECOG E3886: Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D; ECOG. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999 Dec 9;341(24):1781-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; ECOG. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9. link to original article PubMed
  2. RTOG 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. link to original article contains dosing details in abstract PubMed
    1. Update: Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, Venkatesan V, Lawton CA, Rosenthal SA, Sandler HM, Shipley WU. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol. 2008 May 20;26(15):2497-504. Epub 2008 Apr 14. link to original article contains dosing details in manuscript PubMed
    2. Update: Lawton CAF, Lin X, Hanks GE, Lepor H, Grignon DJ, Brereton HD, Bedi M, Rosenthal SA, Zeitzer KL, Venkatesan VM, Horwitz EM, Pisansky TM, Kim H, Parliament MB, Rabinovitch R, Roach M 3rd, Kwok Y, Dignam JJ, Sandler HM. Duration of androgen deprivation in locally advanced prostate cancer: long-term update of NRG Oncology RTOG 9202. Int J Radiat Oncol Biol Phys. 2017 Jun 1;98(2):296-303. Epub 2017 Feb 12. link to original article link to PMC article PubMed
  3. ERADICATE: NCT04484818

Triptorelin & RT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sargos et al. 2020 (GETUG-AFU 17) 2008-2016 Phase 3 (C) Triptorelin & RT; salvage Did not meet primary endpoint of EFS

Statistical power was compromised due to unexpectedly low event rate. GETUG-AFU 17 was published concurrently along with two other Phase 3 trials looking at timing of radiotherapy following radical prostatectomy: RADICALS-RT and ANZUP RAVES. All three trials were also analyzed as part of a pre-planned meta-analysis ARTISTIC which failed to show an EFS benefit with adjuvant radiotherapy vs. salvage radiotherapy.

Preceding treatment

Endocrine therapy

12-week cycle for 2 cycles (6 months)

Radiotherapy

References

  1. GETUG-AFU 17: Sargos P, Chabaud S, Latorzeff I, Magne N, Benyoucef A, Supiot S, Pasquier D, Abdiche MS, Gilliot O, Graff-Cailleaud P, Silva M, Bergerot P, Baumann P, Belkacemi Y, Azria D, Brihoum M, Soulie M, Richaud P. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localized prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol. 2020 Oct; 21(10):1341-1352. link to original article does not contain dosing details PubMed NCT00667069

Salvage ADT & radiotherapy

ADT & RT

ADT & RT: Androgen Deprivation Therapy & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pollack et al. 2022 (SPPORT) 2008-2015 Phase 3 (E-esc) RT Superior FFP (primary endpoint)

Endocrine therapy

Radiotherapy

References

  1. SPPORT: Pollack A, Karrison TG, Balogh AG, Gomella LG, Low DA, Bruner DW, Wefel JS, Martin AG, Michalski JM, Angyalfi SJ, Lukka H, Faria SL, Rodrigues GB, Beauchemin MC, Lee RJ, Seaward SA, Allen AM, Monitto DC, Seiferheld W, Sartor O, Feng F, Sandler HM. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial. Lancet. 2022 May 14;399(10338):1886-1901. link to original article link to PMC article PubMed NCT00567580

Bicalutamide & RT

Bicalutamide & RT: Bicalutamide & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shipley et al. 2017 (RTOG 9601) 1998-2003 Phase 3 (E-esc) RT Seems to have superior OS (primary endpoint)
OS144: 76.3% vs 71.3%
(HR 0.77, 95% CI 0.59-0.99)

Preceding treatment

Endocrine therapy

2-year course

Radiotherapy

7-week course

References

  1. RTOG 9601: Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med. 2017 Feb 2;376(5):417-428. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00002874

Goserelin & RT

Goserelin & RT: Goserelin & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Carrie et al. 2016 (GETUG-AFU 16) 2006-2010 Phase 3 (E-esc) RT Superior PFS (primary endpoint)
PFS60: 80% vs 62%
(HR 0.50, 95% CI 0.38-0.66)

Preceding treatment

Endocrine therapy

3-month cycle for 2 cycles

Radiotherapy

7-week course

References

  1. GETUG-AFU 16: Carrie C, Hasbini A, de Laroche G, Richaud P, Guerif S, Latorzeff I, Supiot S, Bosset M, Lagrange JL, Beckendorf V, Lesaunier F, Dubray B, Wagner JP, N'Guyen TD, Suchaud JP, Créhange G, Barbier N, Habibian M, Ferlay C, Fourneret P, Ruffion A, Dussart S. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol. 2016 Jun;17(6):747-756. Epub 2016 May 6. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. link to original article contains dosing details in abstract PubMed NCT00423475
    1. Update: Carrie C, Magné N, Burban-Provost P, Sargos P, Latorzeff I, Lagrange JL, Supiot S, Belkacemi Y, Peiffert D, Allouache N, Dubray BM, Servagi-Vernat S, Suchaud JP, Crehange G, Guerif S, Brihoum M, Barbier N, Graff-Cailleaud P, Ruffion A, Dussart S, Ferlay C, Chabaud S. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol. 2019 Dec;20(12):1740-1749. Epub 2019 Oct 16. link to original article PubMed
  2. ECOG-ACRIN EA8191: NCT04423211

Hormonal therapy for non-metastatic castrate sensitive disease

ADT

ADT: Androgen Deprivation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oudard et al. 2019 (RisingPSA) 2003-2007 Phase 3 (C) ADT & Docetaxel Did not meet primary endpoint of PSA-PFS
Duchesne et al. 2016 (TOAD) 2004-2012 Phase 3 (E-switch-ic) ADT; delayed Seems to have superior OS (primary endpoint)
OS60: 91.2% vs 86.4%
(HR 0.55, 95% CI 0.30-1.00)
Schulman et al. 2015 (ICELAND) 2006-NR Phase 3 (C) Intermittent ADT Did not meet primary endpoint of TTP

Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Endocrine therapy

12-month course (RisingPSA) or continued indefinitely

References

  1. EORTC 30891: Studer UE, Whelan P, Wimpissinger F, Casselman J, de Reijke TM, Knönagel H, Loidl W, Isorna S, Sundaram SK, Collette L; EORTC Genitourinary Cancer Group. Differences in time to disease progression do not predict for cancer-specific survival in patients receiving immediate or deferred androgen-deprivation therapy for prostate cancer: final results of EORTC randomized trial 30891 with 12 years of follow-up. Eur Urol. 2014 Nov;66(5):829-38. Epub 2013 Jul 24. link to original article PubMed NCT01819285
  2. ICELAND: Schulman C, Cornel E, Matveev V, Tammela TL, Schraml J, Bensadoun H, Warnack W, Persad R, Salagierski M, Gómez Veiga F, Baskin-Bey E, López B, Tombal B. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND). Eur Urol. 2016 Apr;69(4):720-727. Epub 2015 Oct 29. link to original article PubMed NCT00378690
  3. TOAD: Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D'Este C, Frydenberg M, King M, Ledwich L, Loblaw A, Malone S, Millar J, Milne R, Smith RG, Spry N, Stockler M, Syme RA, Tai KH, Turner S. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):727-737. Epub 2016 May 4. Erratum in: Lancet Oncol. 2016 Jun;17 (6):e223. Lancet Oncol. 2017 Sep;18(9):e510. link to original article PubMed NCT00110162
  4. RisingPSA: Oudard S, Latorzeff I, Caty A, Miglianico L, Sevin E, Hardy-Bessard AC, Delva R, Rolland F, Mourey L, Priou F, Beuzeboc P, Gravis G, Linassier C, Gomez P, Voog E, Muracciole X, Abraham C, Banu E, Ferrero JM, Ravaud A, Krakowski I, Lagrange JL, Deplanque G, Zylberait D, Bozec L, Houede N, Culine S, Elaidi R. Effect of adding docetaxel to androgen-deprivation therapy in patients with high-risk prostate cancer with rising prostate-specific antigen levels after primary local therapy: a randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):623-632. Epub 2019 Jan 31. link to original article link to PMC article PubMed NCT00764166

Enzalutamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Freedland et al. 2023 (EMBARK) 2015-01 to 2018-08 Phase 3 (E-RT-switch-ooc) 1. Leuprolide Superior MFS (secondary endpoint)
MFS60: 80% vs 71.4%
(HR 0.63, 95% CI 0.43-0.87)
2. Enzalutamide & Leuprolide Not reported

Endocrine therapy

Continued indefinitely

References

  1. EMBARK: Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, Kim CS, Ramirez-Backhaus M, Rannikko A, Tarazi J, Sridharan S, Sugg J, Tang Y, Tutrone RF Jr, Venugopal B, Villers A, Woo HH, Zohren F, Shore ND. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2023 Oct 19;389(16):1453-1465. link to original article contains dosing details in abstract PubMed NCT02319837
    1. HRQoL analysis: Freedland SJ, Gleave M, De Giorgi U, Rannikko A, Pieczonka CM, Tutrone RF, Venugopal B, Woo HH, Ramirez-Backhaus M, Supiot S, Lantz A, Ganguli A, Ivanova J, Kral P, Huang SP, Saad F, Shore ND. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evidence. 2023 Dec;2(12):EVIDoa2300251. Epub 2023 Oct 22. link to original article PubMed

Enzalutamide & Leuprolide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Freedland et al. 2023 (EMBARK) 2015-01 to 2018-08 Phase 3 (E-RT-esc) 1. Leuprolide Superior MFS (primary endpoint)
MFS60: 87.3% vs 71.4%
(HR 0.42, 95% CI 0.30-0.61)
2. Enzalutamide Not reported

Endocrine therapy

84-day cycles

References

  1. EMBARK: Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, Kim CS, Ramirez-Backhaus M, Rannikko A, Tarazi J, Sridharan S, Sugg J, Tang Y, Tutrone RF Jr, Venugopal B, Villers A, Woo HH, Zohren F, Shore ND. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2023 Oct 19;389(16):1453-1465. link to original article contains dosing details in abstract PubMed NCT02319837
    1. HRQoL analysis: Freedland SJ, Gleave M, De Giorgi U, Rannikko A, Pieczonka CM, Tutrone RF, Venugopal B, Woo HH, Ramirez-Backhaus M, Supiot S, Lantz A, Ganguli A, Ivanova J, Kral P, Huang SP, Saad F, Shore ND. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evidence. 2023 Dec;2(12):EVIDoa2300251. Epub 2023 Oct 22. link to original article PubMed

Leuprolide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Freedland et al. 2023 (EMBARK) 2015-01 to 2018-08 Phase 3 (C) 1. Enzalutamide & Leuprolide
2. Enzalutamide 		Inferior MFS

Endocrine therapy

84-day cycles

References

  1. EMBARK: Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, Haas GP, Kim CS, Ramirez-Backhaus M, Rannikko A, Tarazi J, Sridharan S, Sugg J, Tang Y, Tutrone RF Jr, Venugopal B, Villers A, Woo HH, Zohren F, Shore ND. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2023 Oct 19;389(16):1453-1465. link to original article contains dosing details in abstract PubMed NCT02319837
    1. HRQoL analysis: Freedland SJ, Gleave M, De Giorgi U, Rannikko A, Pieczonka CM, Tutrone RF, Venugopal B, Woo HH, Ramirez-Backhaus M, Supiot S, Lantz A, Ganguli A, Ivanova J, Kral P, Huang SP, Saad F, Shore ND. Enzalutamide and Quality of Life in Biochemically Recurrent Prostate Cancer. NEJM Evidence. 2023 Dec;2(12):EVIDoa2300251. Epub 2023 Oct 22. link to original article PubMed

Hormonal therapy for non-metastatic castrate resistant disease

ADT

ADT: Androgen Deprivation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2017 (SPARTAN) 2013-2016 Phase 3 (C) ADT & Apalutamide Seems to have inferior OS1
Hussain et al. 2018 (PROSPERPrCA) 2013-2017 Phase 3 (C) ADT & Enzalutamide Inferior OS2
Fizazi et al. 2019 (ARAMIS) 2014-2018 Phase 3 (C) ADT & Darolutamide Inferior OS3

1Reported efficacy for SPARTAN is based on the 2020 update.
2Reported efficacy for PROSPER is based on the 2020 update.
3Reported efficacy for ARAMIS is based on the 2020 update.
Note: these are clinical trials that did not specify a particular drug to be used for androgen deprivation. See papers for details.

Endocrine therapy

Continued indefinitely

References

  1. SPARTAN: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. Epub 2018 Feb 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT01946204
    1. HRQoL analysis: Saad F, Cella D, Basch E, Hadaschik BA, Mainwaring PN, Oudard S, Graff JN, McQuarrie K, Li S, Hudgens S, Lawson J, Lopez-Gitlitz A, Yu MK, Smith MR, Small EJ. Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1404-1416. Epub 2018 Sep 10. link to original article PubMed
    2. Update: Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. link to original article link to PMC article PubMed
    3. Update: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158. Epub 2020 Sep 6. link to original article PubMed
  2. PROSPERPrCA: Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. link to original article contains dosing details in abstract link to PMC article PubMed NCT02003924
    1. Update: Sternberg CN, Fizazi K, Saad F, Shore ND, De Giorgi U, Penson DF, Ferreira U, Efstathiou E, Madziarska K, Kolinsky MP, Cubero DIG, Noerby B, Zohren F, Lin X, Modelska K, Sugg J, Steinberg J, Hussain M; PROSPER Investigators. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2197-2206. Epub 2020 May 29. link to original article PubMed
  3. ARAMIS: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. link to original article PubMed NCT02200614
    1. Update: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. link to original article PubMed

ADT & Apalutamide

ADT & Apalutamide: Androgen Deprivation Therapy & Apalutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2017 (SPARTAN) 2013-2016 Phase 3 (E-RT-esc) ADT Superior MFS (primary endpoint)
Median MFS: 40.5 vs 16.2 mo
(HR 0.28, 95% CI 0.23-0.35)

Seems to have superior OS1 (secondary endpoint)
Median OS: 73.9 vs 59.9 mo
(HR 0.78, 95% CI 0.64-0.96)

1Reported efficacy is based on the 2020 update.

Eligibility criteria

  • Castrate-resistant, non-metastatic, PSA doubling time less than 10 months

Endocrine therapy

Continued indefinitely

References

  1. SPARTAN: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. Epub 2018 Feb 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT01946204
    1. HRQoL analysis: Saad F, Cella D, Basch E, Hadaschik BA, Mainwaring PN, Oudard S, Graff JN, McQuarrie K, Li S, Hudgens S, Lawson J, Lopez-Gitlitz A, Yu MK, Smith MR, Small EJ. Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Oct;19(10):1404-1416. Epub 2018 Sep 10. link to original article PubMed
    2. Update: Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Zhang K, Lopez-Gitlitz A, Smith MR. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019 Nov 1;30(11):1813-1820. link to original article link to PMC article PubMed
    3. Update: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158. Epub 2020 Sep 6. link to original article PubMed

ADT & Darolutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fizazi et al. 2019 (ARAMIS) 2014-2018 Phase 3 (E-RT-esc) ADT Superior OS1 (secondary endpoint)
OS36: 83% vs 77%
(HR 0.69, 95% CI 0.53-0.88)

Superior MFS (primary endpoint)
Median MFS: 40.4 vs 18.4 mo
(HR 0.41, 95% CI 0.34-0.50)

1Reported efficacy is based on the 2020 update.

Endocrine therapy

Continued indefinitely

References

  1. ARAMIS: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019 Mar 28;380(13):1235-1246. Epub 2019 Feb 14. link to original article PubMed NCT02200614
    1. Update: Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Le Berre MA, Petrenciuc O, Snapir A, Sarapohja T, Smith MR; ARAMIS Investigators. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020 Sep 10;383(11):1040-1049. link to original article PubMed

ADT & Enzalutamide

ADT & Enzalutamide: Androgen Deprivation Therapy & Enzalutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hussain et al. 2018 (PROSPERPrCA) 2013-2017 Phase 3 (E-RT-esc) ADT Superior OS1 (secondary endpoint)
Median OS: 67 vs 56.3 mo
(HR 0.73, 95% CI 0.61-0.89)

Superior MFS (primary endpoint)
Median MFS: 36.6 vs 14.7 mo
(HR 0.29, 95% CI 0.24-0.35)

1Reported efficacy is based on the 2020 update.

Eligibility criteria

  • Castrate-resistant, non-metastatic, prostate cancer with PSA doubling time less than 10 months

Endocrine therapy

Continued indefinitely

References

  1. PROSPERPrCA: Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, Ivashchenko P, Demirhan E, Modelska K, Phung D, Krivoshik A, Sternberg CN. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2465-2474. link to original article contains dosing details in abstract link to PMC article PubMed NCT02003924
    1. Update: Sternberg CN, Fizazi K, Saad F, Shore ND, De Giorgi U, Penson DF, Ferreira U, Efstathiou E, Madziarska K, Kolinsky MP, Cubero DIG, Noerby B, Zohren F, Lin X, Modelska K, Sugg J, Steinberg J, Hussain M; PROSPER Investigators. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2197-2206. Epub 2020 May 29. link to original article PubMed

Hormonal therapy for metastatic or locally advanced disease

Abarelix monotherapy

Regimen

Study Dates of enrollment Evidence
Koch et al. 2003 NR Non-randomized (RT)

Endocrine therapy

Monthly cycles

References

  1. Koch M, Steidle C, Brosman S, Centeno A, Gaylis F, Campion M, Garnick MB; Abarelix Study Group. An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology. 2003 Nov;62(5):877-82. link to original article PubMed

ADT

ADT: Androgen Deprivation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schröder et al. 2004 (EORTC 30846) 1986-1998 Phase 3 (C) ADT; delayed Did not meet primary endpoint of OS
Fizazi et al. 2015 (GETUG 12) 2002-2006 Phase 3 (C) ADT, Docetaxel, Estramustine Seems to have inferior RFS
Gravis et al. 2013 (GETUG-AFU 15) 2004-2008 Phase 3 (C) ADT & Docetaxel Did not meet primary endpoint of OS
Boevé et al. 2018 (HORRAD) 2004-2014 Phase 3 (C) ADT & RT Did not meet primary endpoint of OS
James et al. 2012 (STAMPEDEcelecoxib) 2005-2011 Phase 3 (C) ADT & Celecoxib Did not meet intermediate primary endpoint of FFS
James et al. 2015 (STAMPEDEdocetaxel) 2005-2011 Phase 3 (C) ADT & Docetaxel Inferior OS
James et al. 2017 (STAMPEDEabiraterone) 2005-2011 Phase 3 (C) ADT & Abiraterone Inferior OS
Sweeney et al. 2015 (CHAARTED) 2006-2012 Phase 3 (C) ADT & Docetaxel Inferior OS1
Kamba et al. 2016 (ZAPCA) 2008-2010 Phase 3 (C) ADT & Zoledronic acid Might have inferior TTTF
Fizazi et al. 2017 (LATITUDE) 2013-02-12 to 2014-12-11 Phase 3 (C) ADT & Abiraterone Inferior OS
Chi et al. 2019 (TITANprostate) 2015-2017 Phase 3 (C) ADT & Apalutamide Inferior OS
Armstrong et al. 2019 (ARCHES) 2016-2018 Phase 3 (C) ADT & Enzalutamide Inferior OS2

1In the 2018 update of CHAARTED, only patients with high-volume disease had inferior survival in the control arm.
2Reported efficacy is based on the 2022 update.
Note: STAMPEDE is a platform RCT; each subtrial is denoted by the therapy used in the experimental arm. These are clinical trials that did not specify a particular therapy to be used for androgen deprivation. See papers for details; the below are examples.

Endocrine therapy

Continued indefinitely

References

  1. EORTC 30846: Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, Debois M, Collette L; European Organisation for the Research and Treatment of Cancer Genito-urinary Group. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol. 2004 Sep;172(3):923-7. link to original article PubMed
  2. STAMPEDEcelecoxib: James ND, Sydes MR, Mason MD, Clarke NW, Anderson J, Dearnaley DP, Dwyer J, Jovic G, Ritchie AW, Russell JM, Sanders K, Thalmann GN, Bertelli G, Birtle AJ, O'Sullivan JM, Protheroe A, Sheehan D, Srihari N, Parmar MK; STAMPEDE Investigators. Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial. Lancet Oncol. 2012 May;13(5):549-58. Epub 2012 Mar 26. Erratum in: Lancet Oncol. 2013 Jan;14(1):e5. link to original article link to PMC article PubMed NCT00268476
  3. GETUG-AFU 15: Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. link to original article PubMed NCT00104715
    1. Update: Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. link to original article PubMed
  4. GETUG 12: Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. link to original article PubMed NCT00055731
  5. CHAARTED: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00309985
    1. Update: Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. link to original article link to PMC article PubMed
    2. HRQoL analysis: Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. link to original article link to PMC article PubMed
  6. STAMPEDEdocetaxel: James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00268476
    1. Update: Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. link to original article link to PMC article PubMed
  7. ZAPCA: Kamba T, Kamoto T, Maruo S, Kikuchi T, Shimizu Y, Namiki S, Fujimoto K, Kawanishi H, Sato F, Narita S, Satoh T, Saito H, Sugimoto M, Teishima J, Masumori N, Egawa S, Sakai H, Okada Y, Terachi T, Ogawa O; ZAPCA Study Group. A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial. Int J Clin Oncol. 2017 Feb;22(1):166-173. Epub 2016 Sep 10. link to original article PubMed NCT00685646
  8. STAMPEDEabiraterone: James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. link to original article link to PMC article supplementary protocol contains dosing details in supplement PubMed NCT00268476
    1. Meta-analysis: Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Amos CL, Atako N, Pugh C, Buckner M, Chowdhury S, Malik Z, Russell JM, Gilson C, Rush H, Bowen J, Lydon A, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzoueb M, Parikh O, Robinson A, Syndikus I, Wylie J, Zarkar A, Thalmann G, de Bono JS, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022 Jan 29;399(10323):447-460. Epub 2021 Dec 23. link to original article PubMed
    2. Update: Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, Hoyle A, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Gilson C, Rush H, Abdel-Aty H, Amos CL, Murphy C, Chowdhury S, Malik Z, Russell JM, Parkar N, Pugh C, Diaz-Montana C, Pezaro C, Grant W, Saxby H, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzouebi M, Parikh O, Robinson A, Montazeri AH, Wylie J, Zarkar A, Cathomas R, Brown MD, Jain Y, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; STAMPEDE investigators. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023 May;24(5):443-456. link to original article PubMed
  9. LATITUDE: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. link to original article supplementary protocol contains dosing details in supplement PubMed NCT01715285
    1. HRQoL analysis: Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. link to original article PubMed
    2. Update: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. link to original article PubMed
  10. HORRAD: Boevé LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019 Mar;75(3):410-418. Epub 2018 Sep 25. link to original article PubMed
  11. TITANprostate: Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. Epub 2019 May 31. link to original article contains dosing details in abstract PubMed NCT02489318
    1. Update: Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Jul 10;39(20):2294-2303. Epub 2021 Apr 29. link to original article PubMed
  12. ARCHES: Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. Epub 2019 Jul 22. link to original article contains dosing details in abstract link to PMC article PubMed NCT02677896

ADT & Abiraterone

ADT & Abiraterone: Androgen Deprivation Therapy & Abiraterone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
James et al. 2017 (STAMPEDEabiraterone) 2005-2011 Phase 3 (E-esc) ADT Superior OS (primary endpoint)
OS36: 83% vs 76%
(HR 0.63, 95% CI 0.52-0.76)
Fizazi et al. 2017 (LATITUDE) 2013-02-12 to 2014-12-11 Phase 3 (E-RT-esc) ADT Superior OS (co-primary endpoint)
Median OS: NYR vs 34.7 mo
(HR 0.62, 95% CI 0.51-0.76)

Note: STAMPEDE is a platform RCT; this subtrial is labeled by the experimental arm additive therapy. While LATITUDE allowed for a dose increase in prednisone, the FDA recommended dose is 5 mg PO once per day.

Endocrine therapy

Supportive therapy

  • Prevention of mineralocorticoid excess with ONE of the following:
    • STAMPEDEabiraterone except Switzerland: Prednisolone (Millipred) 5 mg PO once per day
    • LATITUDE and STAMPEDEabiraterone in Switzerland: Prednisone (Sterapred) 5 mg PO once per day
      • LATITUDE: "dose increase of up to 10 mg/day is permitted to manage refractory mineralocorticoid related toxicities"

Continued indefinitely unless radiotherapy planned, in which case continued for up to 2 years

References

  1. STAMPEDEabiraterone: James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O'Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. Epub 2017 Jun 3. link to original article link to PMC article supplementary protocol contains dosing details in supplement PubMed NCT00268476
    1. Meta-analysis: Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Amos CL, Atako N, Pugh C, Buckner M, Chowdhury S, Malik Z, Russell JM, Gilson C, Rush H, Bowen J, Lydon A, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzoueb M, Parikh O, Robinson A, Syndikus I, Wylie J, Zarkar A, Thalmann G, de Bono JS, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022 Jan 29;399(10323):447-460. Epub 2021 Dec 23. link to original article PubMed
    2. Update: Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, Hoyle A, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Gilson C, Rush H, Abdel-Aty H, Amos CL, Murphy C, Chowdhury S, Malik Z, Russell JM, Parkar N, Pugh C, Diaz-Montana C, Pezaro C, Grant W, Saxby H, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzouebi M, Parikh O, Robinson A, Montazeri AH, Wylie J, Zarkar A, Cathomas R, Brown MD, Jain Y, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; STAMPEDE investigators. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023 May;24(5):443-456. link to original article PubMed
  2. LATITUDE: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 Jul 27;377(4):352-360. Epub 2017 Jun 4. link to original article supplementary protocol contains dosing details in supplement PubMed NCT01715285
    1. HRQoL analysis: Chi KN, Protheroe A, Rodríguez-Antolín A, Facchini G, Suttman H, Matsubara N, Ye Z, Keam B, Damião R, Li T, McQuarrie K, Jia B, De Porre P, Martin J, Todd MB, Fizazi K. Patient-reported outcomes following abiraterone acetate plus prednisone added to androgen deprivation therapy in patients with newly diagnosed metastatic castration-naive prostate cancer (LATITUDE): an international, randomised phase 3 trial. Lancet Oncol. 2018 Feb;19(2):194-206. Epub 2018 Jan 8. link to original article PubMed
    2. Update: Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 May;20(5):686-700. Epub 2019 Apr 12. link to original article PubMed

ADT & Apalutamide

ADT & Apalutamide: Androgen Deprivation Therapy & Apalutamide

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chi et al. 2019 (TITANprostate) 2015-2017 Phase 3 (E-RT-esc) ADT Superior OS1 (co-primary endpoint)
Median OS: NYR vs 52.2 mo
(HR 0.65, 95% CI 0.53-0.79)

1Reported efficacy is based on the 2021 update.
Note: there are several other trials in other cancer subtypes named TITAN.

Endocrine therapy

Continued indefinitely

References

  1. TITANprostate: Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez Soto Á, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. Epub 2019 May 31. link to original article contains dosing details in abstract PubMed NCT02489318
    1. Update: Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021 Jul 10;39(20):2294-2303. Epub 2021 Apr 29. link to original article PubMed

ADT & Bicalutamide

ADT & Bicalutamide: Androgen Deprivation Therapy & Bicalutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davis et al. 2019 (ENZAMET) 2014-2017 Phase 3 (C) ADT & Enzalutamide Inferior OS1
Gu et al. 2022 (CHART) 2018-2020 Phase 3 (C) ADT & Rezvilutamide Inferior OS

1Reported efficacy for ENZAMET is based on the 2023 update.

Endocrine therapy

Continued indefinitely

References

  1. ENZAMET: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. link to original article contains dosing details in supplement PubMed NCT02446405
    1. Update: Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, Chowdhury S, Frydenberg M, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Vera-Badillo F, Williams SG, Winter D, Yip S, Zhang AY, Zielinski RR, Davis ID; ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):323-334. link to original article PubMed
  2. CHART: Gu W, Han W, Luo H, Zhou F, He D, Ma L, Guo H, Liang C, Chong T, Jiang J, Chen Z, Wang Y, Zou Q, Tian Y, Xiao J, Huang J, Zhu S, Dong Q, Zhang X, Li H, Yang X, Chen C, Li J, Jin C, Zhang X, Ye D; CHART Investigators. Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1249-1260. Epub 2022 Sep 5. link to original article contains dosing details in abstract PubMed NCT03520478

ADT, Darolutamide, Docetaxel

ADT, Darolutamide, Docetaxel: Androgen Deprivation Therapy, Darolutamide, Docetaxel

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2022 (ARASENS) 2016-2018 Phase 3 (E-RT-esc) ADT & Docetaxel Superior OS (primary endpoint)
Median OS: NYR vs 48.9 mo
(HR 0.68, 95% CI 0.57-0.80)

Chemotherapy

Endocrine therapy

21-day cycles

References

  1. ARASENS: Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, Kopyltsov E, Park CH, Alekseev B, Montesa-Pino Á, Ye D, Parnis F, Cruz F, Tammela TLJ, Suzuki H, Utriainen T, Fu C, Uemura M, Méndez-Vidal MJ, Maughan BL, Joensuu H, Thiele S, Li R, Kuss I, Tombal B; ARASENS Trial Investigators. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142. Epub 2022 Feb 17. link to original article PubMed NCT02799602

ADT & Docetaxel

ADT & Docetaxel: Androgen Deprivation Therapy & Docetaxel

Regimen variant #1, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
James et al. 2015 (STAMPEDEdocetaxel) 2005-2011 Phase 3 (E-esc) ADT Superior OS (primary endpoint)
Median OS: 81 vs 71 mo
(HR 0.78, 95% CI 0.66-0.93)
Sweeney et al. 2015 (CHAARTED) 2006-2012 Phase 3 (E-esc) ADT Superior OS1 (primary endpoint)
Median OS: 57.6 vs 47.2 mo
(HR 0.72, 95% CI 0.59-0.89)
Smith et al. 2022 (ARASENS) 2016-2018 Phase 3 (C) ADT, Darolutamide, Docetaxel Inferior OS

1Reported efficacy for CHAARTED is for the overall population in the 2018 update; in subgroup analysis, only patients with high-volume disease had superior survival in the experimental arm.
Note: STAMPEDE is a platform RCT; this subtrial is labeled by the experimental arm additive therapy. Patients already on androgen deprivation therapy were eligible to participate in CHAARTED if there was no evidence of disease progression and if they had started ADT no more than 120 days before randomization.

Chemotherapy

Endocrine therapy

Supportive therapy

  • Dexamethasone (Decadron) 8 mg PO given three times; 12 hours, 3 hours, and 1 hour prior to docetaxel
  • Daily prednisone was not required
  • At least calcium 500 mg and vitamin D 400 IU PO once per day

21-day cycle for up to 6 cycles


Regimen variant #2, 9 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gravis et al. 2013 (GETUG-AFU 15) 2004-2008 Phase 3 (E-esc) ADT Did not meet primary endpoint of OS
Median OS: 58.9 vs 54.2 mo
(HR 1.01, 95% CI 0.75-1.36)

Chemotherapy

Endocrine therapy

21-day cycle for up to 9 cycles

References

  1. GETUG-AFU 15: Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Pouessel D, Mourey L, Beuzeboc P, Zanetta S, Habibian M, Berdah JF, Dauba J, Baciuchka M, Platini C, Linassier C, Labourey JL, Machiels JP, El Kouri C, Ravaud A, Suc E, Eymard JC, Hasbini A, Bousquet G, Soulie M. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):149-58. Epub 2013 Jan 8. link to original article PubMed NCT00104715
    1. Update: Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Théodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: Impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016 Aug;70(2):256-62. Epub 2015 Nov 21. link to original article PubMed
  2. CHAARTED: Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. Epub 2015 Aug 5. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00309985
    1. Update: Kyriakopoulos CE, Chen YH, Carducci MA, Liu G, Jarrard DF, Hahn NM, Shevrin DH, Dreicer R, Hussain M, Eisenberger M, Kohli M, Plimack ER, Vogelzang NJ, Picus J, Cooney MM, Garcia JA, DiPaola RS, Sweeney CJ. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018 Apr 10;36(11):1080-1087. Epub 2018 Jan 31. link to original article link to PMC article PubMed
    2. HRQoL analysis: Morgans AK, Chen YH, Sweeney CJ, Jarrard DF, Plimack ER, Gartrell BA, Carducci MA, Hussain M, Garcia JA, Cella D, DiPaola RS, Patrick-Miller LJ. Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer. J Clin Oncol. 2018 Apr 10;36(11):1088-1095. Epub 2018 Mar 9. link to original article link to PMC article PubMed
  3. STAMPEDEdocetaxel: James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK; STAMPEDE Investigators. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1163-77. Epub 2015 Dec 21. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00268476
    1. Update: Clarke NW, Ali A, Ingleby FC, Hoyle A, Amos CL, Attard G, Brawley CD, Calvert J, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert D, Gillessen S, Jones RJ, Langley RE, MacNair A, Malik Z, Mason MD, Matheson D, Millman R, Parker CC, Ritchie AWS, Rush H, Russell JM, Brown J, Beesley S, Birtle A, Capaldi L, Gale J, Gibbs S, Lydon A, Nikapota A, Omlin A, O'Sullivan JM, Parikh O, Protheroe A, Rudman S, Srihari NN, Simms M, Tanguay JS, Tolan S, Wagstaff J, Wallace J, Wylie J, Zarkar A, Sydes MR, Parmar MKB, James ND. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019 Dec 1;30(12):1992-2003. link to original article link to PMC article PubMed
  4. ARASENS: Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, Kopyltsov E, Park CH, Alekseev B, Montesa-Pino Á, Ye D, Parnis F, Cruz F, Tammela TLJ, Suzuki H, Utriainen T, Fu C, Uemura M, Méndez-Vidal MJ, Maughan BL, Joensuu H, Thiele S, Li R, Kuss I, Tombal B; ARASENS Trial Investigators. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142. Epub 2022 Feb 17. link to original article PubMed NCT02799602
  5. PEACE-1: Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fléchon A, Tombal B, Supiot S, Berthold D, Ronchin P, Kacso G, Gravis G, Calabro F, Berdah JF, Hasbini A, Silva M, Thiery-Vuillemin A, Latorzeff I, Mourey L, Laguerre B, Abadie-Lacourtoisie S, Martin E, El Kouri C, Escande A, Rosello A, Magne N, Schlurmann F, Priou F, Chand-Fouche ME, Freixa SV, Jamaluddin M, Rieger I, Bossi A; PEACE-1 investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022 Apr 30;399(10336):1695-1707. Epub 2022 Apr 8. link to original article PubMed NCT01957436

ADT & Enzalutamide

ADT & Enzalutamide: Androgen Deprivation Therapy & Enzalutamide

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davis et al. 2019 (ENZAMET) 2014-2017 Phase 3 (E-switch-ic) 1a. ADT & Bicalutamide
1b. ADT & Flutamide
1c. ADT & Niluatmide 		Superior OS1 (primary endpoint)
OS60: 67% vs 57%
(HR 0.70, 95% CI 0.58-0.84)
Armstrong et al. 2019 (ARCHES) 2016-2018 Phase 3 (E-RT-esc) ADT Superior OS2 (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.66, 95% CI 0.53-0.81)

Superior rPFS (primary endpoint)
Median rPFS: NYR vs 19 mo
(HR 0.39, 95% CI 0.30-0.50)
Agarwal et al. 2023 (TALAPRO-2) 2019-01-07 to 2020-09-17 Phase 3 (C) ADT, Enzalutamide, Talazoparib Inferior rPFS

1Reported efficacy for ENZAMET is based on the 2023 update.
2Reported efficacy for ARCHES is based on the 2022 update.

Endocrine therapy

Continued indefinitely

References

  1. ENZAMET: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. link to original article contains dosing details in abstract PubMed NCT02446405
    1. Update: Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, Chowdhury S, Frydenberg M, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Vera-Badillo F, Williams SG, Winter D, Yip S, Zhang AY, Zielinski RR, Davis ID; ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):323-334. link to original article PubMed
  2. ARCHES: Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. Epub 2019 Jul 22. link to original article contains dosing details in abstract link to PMC article PubMed NCT02677896
    1. HRQoL analysis: Stenzl A, Dunshee C, De Giorgi U, Alekseev B, Iguchi T, Szmulewitz RZ, Flaig TW, Tombal B, Morlock R, Ivanescu C, Ramaswamy K, Saad F, Armstrong AJ. Effect of Enzalutamide plus Androgen Deprivation Therapy on Health-related Quality of Life in Patients with Metastatic Hormone-sensitive Prostate Cancer: An Analysis of the ARCHES Randomised, Placebo-controlled, Phase 3 Study. Eur Urol. 2020 Oct;78(4):603-614. Epub 2020 Apr 23. link to original article PubMed
    2. Update: Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Alcaraz A, Alekseev B, Shore ND, Gomez-Veiga F, Rosbrook B, Zohren F, Yamada S, Haas GP, Stenzl A. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022 May 20;40(15):1616-1622. Epub 2022 Apr 14. link to original article link to PMC article PubMed
  3. TALAPRO-2: Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, Szczylik C, De Giorgi U, Young Joung J, Fong PCC, Voog E, Jones RJ, Shore ND, Dunshee C, Zschäbitz S, Oldenburg J, Lin X, Healy CG, Di Santo N, Zohren F, Fizazi K. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jul 22;402(10398):291-303. Epub 2023 Jun 4. Erratum in: Lancet. 2023 Jul 22;402(10398):290. link to original article contains dosing details in abstract PubMed NCT03395197

ADT, Enzalutamide, Talazoparib

ADT, Enzalutamide, Talazoparib: Androgen Deprivation Therapy, Enzalutamide, Talazoparib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Agarwal et al. 2023 (TALAPRO-2) 2019-01-07 to 2020-09-17 Phase 3 (E-esc) ADT & Enzalutamide Superior rPFS (primary endpoint)
Median rPFS: NYR vs 21.9 mo
(HR 0.63, 95% CI 0.51-0.78)

Endocrine therapy

Targeted therapy

Continued indefinitely

References

  1. TALAPRO-2: Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, Szczylik C, De Giorgi U, Young Joung J, Fong PCC, Voog E, Jones RJ, Shore ND, Dunshee C, Zschäbitz S, Oldenburg J, Lin X, Healy CG, Di Santo N, Zohren F, Fizazi K. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jul 22;402(10398):291-303. Epub 2023 Jun 4. Erratum in: Lancet. 2023 Jul 22;402(10398):290. link to original article contains dosing details in abstract PubMed NCT03395197

ADT & Flutamide

ADT & Flutamide: Androgen Deprivation Therapy & Flutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davis et al. 2019 (ENZAMET) 2014-2017 Phase 3 (C) ADT & Enzalutamide Inferior OS1

1Reported efficacy is based on the 2023 update.

Endocrine therapy

Continued indefinitely

References

  1. ENZAMET: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. link to original article contains dosing details in supplement PubMed NCT02446405
    1. Update: Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, Chowdhury S, Frydenberg M, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Vera-Badillo F, Williams SG, Winter D, Yip S, Zhang AY, Zielinski RR, Davis ID; ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):323-334. link to original article PubMed

ADT & Nilutamide

ADT & Nilutamide: Androgen Deprivation Therapy & Nilutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davis et al. 2019 (ENZAMET) 2014-2017 Phase 3 (C) ADT & Enzalutamide Inferior OS1

1Reported efficacy is based on the 2023 update.

Endocrine therapy

Continued indefinitely

References

  1. ENZAMET: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. Epub 2019 Jun 2. link to original article contains dosing details in supplement PubMed NCT02446405
    1. Update: Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, Chowdhury S, Frydenberg M, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Vera-Badillo F, Williams SG, Winter D, Yip S, Zhang AY, Zielinski RR, Davis ID; ENZAMET trial investigators and Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):323-334. link to original article PubMed

Bicalutamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tyrrell et al. 1998 NR in abstract Phase 3 (E-switch-ic) Castration Did not meet co-primary endpoints of PFS/OS1
Iversen et al. 2002 (SPCG-6) 1995-1998 Phase 3 (E-esc) Placebo Superior OS2
(HR 0.77, 95% CI 0.63-0.94)

1Reported efficacy for Tyrrell et al. 1998 is based on the 2000 update.
2Reported efficacy for SPCG-6 is based on the 2015 update and is only for the locally advanced subgroup.
Note: Bicalutamide is not approved for monotherapy in the United States. See combination regimens with goserelin & leuprolide.

Endocrine therapy

Continued indefinitely

References

  1. Tyrrell CJ, Kaisary AV, Iversen P, Anderson JB, Baert L, Tammela T, Chamberlain M, Webster A, Blackledge G. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol. 1998;33(5):447-56. link to original article contains dosing details in abstract PubMed
    1. Update: Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol. 2000 Nov;164(5):1579-82. link to original article contains dosing details in manuscript PubMed
  2. SPCG-6: Iversen P, Tammela TL, Vaage S, Lukkarinen O, Lodding P, Bull-Njaa T, Viitanen J, Hoisaeter P, Lundmo P, Rasmussen F, Johansson JE, Persson BE, Carroll K; Scandinavian Prostatic Cancer Group. A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer: first report from the Scandinavian Prostatic Cancer Group Study No 6. Eur Urol. 2002 Sep;42(3):204-11. link to original article PubMed NCT00672282
    1. Update: Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K; Scandinavian Prostatic Cancer Group. Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. J Urol. 2004 Nov;172(5 Pt 1):1871-6. link to original article PubMed
    2. Update: Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J; Scandinavian Prostate Cancer Group. Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scand J Urol Nephrol. 2006;40(6):441-52. link to original article PubMed
    3. Update: Thomsen FB, Brasso K, Christensen IJ, Johansson JE, Angelsen A, Tammela TL, Iversen P; Scandinavian Prostate Cancer Group. Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer: long-term follow-up of the SPCG-6 study. Eur J Cancer. 2015 Jul;51(10):1283-92. Epub 2015 Apr 16. link to original article PubMed

Bicalutamide & Goserelin

Regimen variant #1, 50/3.6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schellhammer et al. 1995 1992-01 to 1993-09 Phase 3 (E-RT-switch-ic) 1. Bicalutamide & Leuprolide Not reported
2. Flutamide & Goserelin
3. Flutamide & Leuprolide 		Equivalent TTP1

1Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Endocrine therapy

28-day cycles


Regimen variant #2, 80/3.6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Akaza et al. 2004 2000-02 to 2001-12 Phase 3 (E-esc) 1. Goserelin
2. Leuprolide 		Seems to have superior OS1 (secondary endpoint)

Superior 12-week PSA normalization rate (primary endpoint)

1Reported efficacy is based on the 2009 update.

Endocrine therapy

28-day cycles

References

  1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. link to original article PubMed
    1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains dosing details in abstract PubMed
    2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. link to original article contains dosing details in abstract PubMed
    3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
  2. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed

Bicalutamide & Leuprolide

Regimen variant #1, 50 + 1 mo depot

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schellhammer et al. 1995 1992-01 to 1993-09 Phase 3 (E-RT-switch-ic) 1. Bicalutamide & Goserelin Not reported
2. Flutamide & Goserelin
3. Flutamide & Leuprolide 		Equivalent TTP1
Trachtenberg et al. 2002 NR Phase 3 (C) Abarelix Inferior primary endpoint

1Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Endocrine therapy

28-day cycles


Regimen variant #2, 50 + 3 mo depot

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Agarwal et al. 2022 (SWOG S1216) 2013-2017 Phase 3 (C) ADT & Orteronel Did not meet primary endpoint of OS

Endocrine therapy

90-day cycles


Regimen variant #3, 80 + 1 mo depot

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Akaza et al. 2004 2000-02 to 2001-12 Phase 3 (E-esc) 1. Goserelin
2. Leuprolide 		Seems to have superior OS1 (secondary endpoint)

1Reported efficacy is based on the 2009 update.

Endocrine therapy

28-day cycles

References

  1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. link to original article PubMed
    1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains dosing details in abstract PubMed
    2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. link to original article contains dosing details in abstract PubMed
    3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
  2. Trachtenberg J, Gittleman M, Steidle C, Barzell W, Friedel W, Pessis D, Fotheringham N, Campion M, Garnick MB; Abarelix Study Group. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol. 2002 Apr;167(4):1670-4. link to original article contains dosing details in abstract PubMed
  3. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed
  4. SWOG S1216: Agarwal N, Tangen CM, Hussain MHA, Gupta S, Plets M, Lara PN, Harzstark AL, Twardowski PW, Paller CJ, Zylla D, Zibelman MR, Levine E, Roth BJ, Goldkorn A, Vaena DA, Kohli M, Crispino T, Vogelzang NJ, Thompson IM Jr, Quinn DI. Orteronel for Metastatic Hormone-Sensitive Prostate Cancer: A Multicenter, Randomized, Open-Label Phase III Trial (SWOG-1216). J Clin Oncol. 2022 Oct 1;40(28):3301-3309. Epub 2022 Apr 21. link to original article link to PMC article PubMed NCT01809691
    1. Subgroup analysis: Sayegh N, Swami U, Jo Y, Gebrael G, Haaland B, Gupta S, Plets M, Hussain MHA, Quinn DI, Lara PN Jr, Thompson IM Jr, Agarwal N. Race and Treatment Outcomes in Patients With Metastatic Castration-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG 1216 Phase 3 Trial. JAMA Netw Open. 2023 Aug 1;6(8):e2326546. link to original article link to PMC article PubMed

Degarelix monotherapy

Example orders

Regimen variant #1, 240/80

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Klotz et al. 2008 (CS21) 2006-02 to 2007-10 Phase 3 (E-RT-switch-ic) 1. Degarelix; 240/160 Non-inferior testosterone suppression (primary endpoint)
2. Leuprolide Non-inferior testosterone suppression (primary endpoint)

Endocrine therapy

  • Degarelix (Firmagon) as follows:
    • Cycle 1: 240 mg SC once on day 1
    • Cycle 2 onwards: 80 mg SC once on day 1

28-day cycles


Regimen variant #2, 240/160

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Klotz et al. 2008 (CS21) 2006-02 to 2007-10 Phase 3 (E-RT-switch-ic) 1. Degarelix; 240/80 Non-inferior testosterone suppression (primary endpoint)
2. Leuprolide Non-inferior testosterone suppression (primary endpoint)

Endocrine therapy

  • Degarelix (Firmagon) as follows:
    • Cycle 1: 240 mg SC once on day 1
    • Cycle 2 onwards: 160 mg SC once on day 1

28-day cycles


Regimen variant #3, 240/480

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ozono et al. 2018 (3550-CL-0010) 2013-NR Phase 3 (E-switch-ic) Goserelin Non-inferior testosterone suppression (primary endpoint)

Endocrine therapy

  • Degarelix (Firmagon) as follows:
    • Cycle 1: 240 mg SC once on day 1
    • Cycle 2 onwards: 480 mg SC once on day 1

28-day course, then 12-week cycles

References

  1. CS21: Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. link to original article contains dosing details in manuscript PubMed NCT00295750
    1. Update: Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. link to original article contains dosing details in manuscript PubMed
  2. 3550-CL-0010: Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. link to original article link to PMC article PubMed NCT01964170

Docetaxel, Estramustine, Goserelin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fizazi et al. 2015 (GETUG 12) 2002-2006 Phase 3 (E-esc) ADT Superior RFS (primary endpoint)
RFS96: 62% vs 50%
(HR 0.71, 95% CI 0.54-0.94)

Chemotherapy

21-day cycle for 4 cycles

Endocrine therapy

3-month cycle for 12 cycles (3 years)

References

  1. GETUG 12: Fizazi K, Faivre L, Lesaunier F, Delva R, Gravis G, Rolland F, Priou F, Ferrero JM, Houede N, Mourey L, Theodore C, Krakowski I, Berdah JF, Baciuchka M, Laguerre B, Fléchon A, Ravaud A, Cojean-Zelek I, Oudard S, Labourey JL, Chinet-Charrot P, Legouffe E, Lagrange JL, Linassier C, Deplanque G, Beuzeboc P, Davin JL, Martin AL, Habibian M, Laplanche A, Culine S. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015 Jul;16(7):787-94. Epub 2015 May 28. link to original article contains dosing details in abstract PubMed NCT00055731

Flutamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Boccon-Gibod et al. 1997 1989-1991 Phase 3 (E-switch-ic) Bilateral orchiectomy Did not meet primary endpoint of PFS
Fosså et al. 2001 (EORTC 30903) 1992-1998 Phase 3 (E-switch-ic) Prednisone Did not meet co-primary endpoints of TTP/OS

Note: Flutamide is not approved for monotherapy in the United States. See combination regimens with goserelin & leuprolide.

Endocrine therapy

Continued indefinitely

References

  1. Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P, Hubert J, Soret JY, Mangin P, Mallo C, Fraysse CE. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5. link to original article contains dosing details in abstract PubMed
  2. EORTC 30903: Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. link to original article contains dosing details in abstract PubMed

Flutamide & Goserelin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iversen et al. 1990 1986-06 to 1987-12 Phase 3 (E-switch-ic) Bilateral orchiectomy Did not meet co-primary endpoints of OS/PFS/TTP
Keuppens et al. 1990 (EORTC 30853) 1986-1988 Phase 3 (E-switch-ic) Bilateral orchiectomy Seems to have superior OS1
Schellhammer et al. 1995 1992-01 to 1993-09 Phase 3 (C) 1. Bicalutamide & Goserelin
2. Bicalutamide & Leuprolide 		Equivalent TTP2
3. Flutamide & Leuprolide Not reported
Hussain et al. 2013 (SWOG-9346) 1995-2008 Phase 3 (C) Intermittent ADT Inconclusive whether non-inferior OS

1Reported efficacy for EORTC 30853 is based on the 1998 final update.
2Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Endocrine therapy

28-day cycles

References

  1. EORTC 30853: Keuppens F, Denis L, Smith P, Carvalho AP, Newling D, Bond A, Sylvester R, De Pauw M, Vermeylen K, Ongena P; EORTC GU Group. Zoladex and flutamide versus bilateral orchiectomy: a randomized phase III EORTC 30853 study. Cancer. 1990 Sep 1;66(5 Suppl):1045-57. link to original article PubMed
    1. Update: Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, De Pauw M; EORTC GU Group. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology. 1993 Aug;42(2):119-29. link to original article contains dosing details in abstract PubMed
    2. Update: Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R; EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol. 1998;33(2):144-51. link to original article PubMed
  2. Iversen P, Christensen MG, Friis E, Hornbøl P, Hvidt V, Iversen HG, Klarskov P, Krarup T, Lund F, Mogensen P, Pedersen T, Rasmussen F, Rose C, Skaarup P, Wolf H. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer. 1990 Sep 1;66(5 Suppl):1058-66. link to original article contains dosing details in manuscript PubMed
  3. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. link to original article PubMed
    1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains dosing details in abstract PubMed
    2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. link to original article contains dosing details in abstract PubMed
    3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
  4. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains dosing details in supplement PubMed NCT00002651

Flutamide & Leuprolide

Regimen variant #1, daily Lupron

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Crawford et al. 1989 (SWOG-8494) 1985-01 to 1986-04 Phase 3 (E-RT-esc) Leuprolide Seems to have superior OS

Note: this is likely of historic importance only, given the formulation of leuoprolide.

Endocrine therapy

Continued indefinitely


Regimen variant #2, 1-month depot Lupron

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schellhammer et al. 1995 1992-01 to 1993-09 Phase 3 (C) 1. Bicalutamide & Goserelin
2. Bicalutamide & Leuprolide 		Equivalent TTP1
3. Flutamide & Goserelin Not reported
Hussain et al. 2013 (SWOG-9346) 1995-2008 Phase 3 (C) Intermittent ADT Inconclusive whether non-inferior OS

1Reported efficacy for Schellhammer et al. 1995 is based on the 1997 final update.

Endocrine therapy

28-day cycles

References

  1. SWOG-8494: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. link to original article contains dosing details in manuscript PubMed
  2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology. 1995 May;45(5):745-52. link to original article PubMed
    1. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Chen Y, Kolvenbag GJ; CASODEX Combination Study Group. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: analysis of time to progression. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains dosing details in abstract PubMed
    2. Update: Soloway MS, Schellhammer P, Sharifi R, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G; Casodex Combination Study Group. A controlled trial of Casodex (bicalutamide) vs flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Eur Urol. 1996;29 Suppl 2:105-9. link to original article contains dosing details in abstract PubMed
    3. Update: Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ; Casodex Combination Study Group. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology. 1997 Sep;50(3):330-6. link to original article PubMed
  3. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains dosing details in supplement PubMed NCT00002651

Goserelin monotherapy

Example orders

Regimen variant #1, 28-day cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Soloway et al. 1991 NR Phase 3 (E-switch-ic) Bilateral orchiectomy Did not meet efficacy endpoints
Kaisary et al. 1991 1983-1986 Phase 3 (E-switch-ic) Bilateral orchiectomy Did not meet efficacy endpoints
Waymont et al. 1992 1985-1987 Phase 3 (E-switch-ic) DES Seems to have superior time to first response
Tyrrell et al. 1991 (IPCSG) 1986-01 to 1987-07 Phase 3 (C) Flutamide & Goserelin Did not meet efficacy endpoints
Boccardo et al. 1993 (PONCAP) 1987-1990 Phase 3 (C) Flutamide & Goserelin Might have inferior PFS50%

Endocrine therapy

28-day cycles


Regimen variant #2, 12-week cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ozono et al. 2018 (3550-CL-0010) 2013-NR Phase 3 (C) Degarelix Non-inferior testosterone suppression

Endocrine therapy

  • Goserelin (Zoladex) as follows:
    • Cycle 1: 3.6 mg SC once on day 1
    • Cycle 2 onwards: 10.8 mg SC once on day 1

28-day course, then 12-week cycles

References

  1. Soloway MS, Chodak G, Vogelzang NJ, Block NL, Schellhammer PF, Smith JA Jr, Scott M, Kennealey G, Gau TC; Zoladex Prostate Study Group. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology. 1991 Jan;37(1):46-51. link to original article PubMed
    1. Update: Vogelzang NJ, Chodak GW, Soloway MS, Block NL, Schellhammer PF, Smith JA Jr, Caplan RJ, Kennealey GT; Zoladex Prostate Study Group. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology. 1995 Aug;46(2):220-6. link to original article contains dosing details in manuscript PubMed
  2. Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol. 1991 May;67(5):502-8. link to original article PubMed
  3. IPCSG: Tyrrell CJ, Altwein JE, Klippel F, Varenhorst E, Lunglmayr G, Boccardo F, Holdaway IM, Haefliger JM, Jordaan JP; International Prostate Cancer Study Group. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol. 1991 Nov;146(5):1321-6. link to original article PubMed
  4. Waymont B, Lynch TH, Dunn JA, Emtage LA, Arkell DG, Wallace DM, Blackledge GR. Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol. 1992 Jun;69(6):614-20. link to original article PubMed
  5. PONCAP: Boccardo F, Pace M, Rubagotti A, Guarneri D, Decensi A, Oneto F, Martorana G, Giuliani L, Selvaggi F, Battaglia M, Delli Ponti U, Petracco S, Cortellini P, Ziveri M, Ferraris V, Bruttini GP, Epis R, Comeri G, Gallo G; Italian Prostatic Cancer Project (PONCAP) Study Group. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostate cancer. Eur J Cancer. 1993;29A(8):1088-93. link to original article PubMed
  6. 3550-CL-0010: Ozono S, Tsukamoto T, Naito S, Horie S, Ohashi Y, Uemura H, Yokomizo Y, Fukasawa S, Kusuoka H, Akazawa R, Saito M, Akaza H. Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: a phase III study. Cancer Sci. 2018 Jun;109(6):1920-1929. Epub 2018 May 23. link to original article link to PMC article PubMed NCT01964170

Histrelin monotherapy

Regimen

Study Dates of enrollment Evidence
Schlegel 2006 NR Non-randomized (RT)

Endocrine therapy

References

  1. Schlegel PN; Histrelin Study Group. Efficacy and safety of histrelin subdermal implant in patients with advanced prostate cancer. J Urol. 2006 Apr;175(4):1353-8. link to original article PubMed

Intermittent ADT

IHT: Intermittent Hormone Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Calais da Silva et al. 2009 (SEUG 9401) NR Phase 3 (E-de-esc) Continuous ADT Did not meet primary endpoint of TTP
Hussain et al. 2013 (SWOG-9346) 1995-2008 Phase 3 (E-de-esc) Continuous ADT Inconclusive whether non-inferior OS (co-primary endpoint)
Crook et al. 2012 (NCIC-CTG PR.7) 1999-2005 Phase 3 (E-de-esc) Continuous ADT Non-inferior OS (primary endpoint)
Median OS: 8.8 vs 9.1 y
(HR 1.02, 95% CI 0.86-1.21)
Calais da Silva et al. 2013 (SEUG 9901) 2000-2007 Phase 3 (E-de-esc) Continuous ADT Non-inferior OS (primary endpoint)

Note: See papers for details about treatment holidays.

Endocrine therapy

8-month cycles

References

  1. SEUG 9401: Calais da Silva FE, Bono AV, Whelan P, Brausi M, Marques Queimadelos A, Martin JA, Kirkali Z, Calais da Silva FM, Robertson C. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009 Jun;55(6):1269-77. Epub 2009 Feb 21. link to original article PubMed
  2. NCIC-CTG PR.7: Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012 Sep 6;367(10):895-903. Erratum in: N Engl J Med. 2012 Dec 6;367(23):2262. link to original article link to PMC article PubMed NCT00003653
  3. SWOG-9346: Hussain M, Tangen CM, Berry DL, Higano CS, Crawford ED, Liu G, Wilding G, Prescott S, Kanaga Sundaram S, Small EJ, Dawson NA, Donnelly BJ, Venner PM, Vaishampayan UN, Schellhammer PF, Quinn DI, Raghavan D, Ely B, Moinpour CM, Vogelzang NJ, Thompson IM Jr. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25. link to original article link to PMC article supplementary protocol contains dosing details in supplement PubMed NCT00002651
  4. SEUG 9901: Calais da Silva F, Calais da Silva FM, Gonçalves F, Santos A, Kliment J, Whelan P, Oliver T, Antoniou N, Pastidis S, Marques Queimadelos A, Robertson C. Locally advanced and metastatic prostate cancer treated with intermittent androgen monotherapy or maximal androgen blockade: results from a randomised phase 3 study by the South European Uroncological Group. Eur Urol. 2014 Aug;66(2):232-9. Epub 2013 Apr 4. link to original article PubMed NCT00363285

Leuprolide monotherapy

Example orders

Regimen variant #1, daily

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Garnick et al. 1984 1981-NR Phase 3 (E-switch-ic) DES Did not meet efficacy endpoints Less toxic
Crawford et al. 1989 (SWOG-8494) 1985-01 to 1986-04 Phase 3 (C) Flutamide & Leuprolide Seems to have inferior OS

Note: this is of historic importance only, given the wide availability of depot formulations of leuoprolide.

Endocrine therapy

Continued indefinitely


Regimen variant #2, 1-month depot, 3.75 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Akaza et al. 2004 2000-02 to 2001-12 Phase 3 (C) 1. Bicalutamide & Goserelin
2. Bicalutamide & Leuprolide 		Seems to have inferior OS1

1Reported efficacy is based on the 2009 update.

Endocrine therapy

28-day cycles


Regimen variant #3, 1-month depot, 7.5 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sharifi & Soloway 1990 1986-NR Non-randomized (RT)
Heyns et al. 2003 NR Phase 3 (C) Triptorelin Seems to have inferior 9-month OS
Klotz et al. 2008 (CS21) 2006-02 to 2007-10 Phase 3 (C) 1. Degarelix; 240/80 Non-inferior testosterone suppression (primary endpoint)
2. Degarelix; 240/160 Non-inferior testosterone suppression (primary endpoint)

Endocrine therapy

28-day cycles


Regimen variant #4, 3-month depot

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sharifi et al. 1996 NR Phase 2 (RT)
Shore et al. 2020 (HERO) 2017-04 to 2018-10 Phase 3 (C) Relugolix Inferior testosterone suppression

Endocrine therapy

84-day cycles


Regimen variant #5, 4-month depot

Study Dates of enrollment Evidence
Sharifi et al. 1998 NR Phase 2 (RT)

Endocrine therapy

16-week cycles


Regimen variant #6, 6-month depot

Study Dates of enrollment Evidence
Spitz et al. 2011 (L-PC07-169) 2008-2009 Non-randomized phase 3 (RT)

Endocrine therapy

26-week cycles

References

  1. Garnick MB, Glode LM; Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med. 1984 Nov 15;311(20):1281-6. link to original article contains dosing details in abstract PubMed
  2. SWOG-8494: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989 Aug 17;321(7):419-24. Erratum in: N Engl J Med 1989 Nov 16;321(20):1420. link to original article contains dosing details in manuscript PubMed
  3. Sharifi R, Soloway M; Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol. 1990 Jan;143(1):68-71. link to original article PubMed
  4. Sharifi R, Bruskewitz RC, Gittleman MC, Graham SD Jr, Hudson PB, Stein B. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther. 1996 Jul-Aug;18(4):647-57. link to original article contains dosing details in manuscript PubMed
  5. Sharifi R, Knoll LD, Smith J, Kramolowsky E. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urology. 1998 Feb;51(2):271-6. link to original article PubMed
  6. Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC; South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003 Aug;92(3):226-31. link to original article contains dosing details in abstract PubMed
  7. Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y. Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol. 2004 Jan;34(1):20-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S, Hirao Y; Study Group for the Combined Androgen Blockade Therapy of Prostate Cancer. Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer. 2009 Aug 1;115(15):3437-45. link to original article PubMed
  8. CS21: Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8. link to original article contains dosing details in manuscript PubMed NCT00295750
    1. Update: Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, Kold Olesen T, Persson BE. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010 May;57(5):836-42. Epub 2009 Nov 20. link to original article contains dosing details in manuscript PubMed
  9. L-PC07-169: Spitz A, Young JM, Larsen L, Mattia-Goldberg C, Donnelly J, Chwalisz K. Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer. Prostate Cancer Prostatic Dis. 2012 Mar;15(1):93-9. Epub 2011 Oct 25. link to original article link to PMC article PubMed NCT00626431
  10. HERO: Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. Epub 2020 May 29. link to original article contains dosing details in manuscript PubMed NCT03085095
    1. HRQoL analysis: Tombal B, Collins S, Morgans AK, Hunsche E, Brown B, Zhu E, Bossi A, Shore N. Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study. Eur Urol. 2023 Dec;84(6):579-587. Epub 2023 Oct 11. link to original article PubMed

Nilutamide & Orchiectomy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Janknegt et al. 1993 (International Anandron Study) 1986-NR Phase 3 (E-RT-esc) Bilateral orchiectomy Superior PFS

Note: Nilutamide was to start the day of, or day after surgical castration/orchiectomy.

Endocrine therapy

One-month cycles

References

  1. International Anandron Study: Janknegt RA, Abbou CC, Bartoletti R, Bernstein-Hahn L, Bracken B, Brisset JM, Da Silva FC, Chisholm G, Crawford ED, Debruyne FM, Dijkman GD, Frick J, Goedhals J, Knönagel H, Venner PM. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol. 1993 Jan;149(1):77-82. link to original article PubMed
    1. Update: Janknegt RA; Anandron International Study Group. Total androgen blockade with the use of orchiectomy and nilutamide (Anandron) or placebo as treatment of metastatic prostate cancer. Cancer. 1993 Dec 15;72(12 Suppl):3874-7. link to original article PubMed
    2. Update: Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM; International Anandron Study Group. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. J Urol. 1997 Jul;158(1):160-3. link to original article PubMed
    3. Update: de Reijke T, Derobert E; Anandron /Nilutamide Study Group. Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: a final update. Eur Urol. 2002 Aug;42(2):139-46. link to original article contains dosing details in manuscript PubMed

Relugolix monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shore et al. 2020 (HERO) 2017-04 to 2018-10 Phase 3 (E-RT-switch-ic) Leuprolide Superior testosterone suppression (primary endpoint)

Endocrine therapy

48-week course

References

  1. HERO: Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, van Veenhuyzen DF, Selby B, Fan X, Kang V, Walling J, Tombal B; HERO Study Investigators. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2187-2196. Epub 2020 May 29. link to original article contains dosing details in manuscript PubMed NCT03085095
    1. HRQoL analysis: Tombal B, Collins S, Morgans AK, Hunsche E, Brown B, Zhu E, Bossi A, Shore N. Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study. Eur Urol. 2023 Dec;84(6):579-587. Epub 2023 Oct 11. link to original article PubMed

Triptorelin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heyns et al. 2003 NR Phase 3 (E-RT-switch-ic) Leuprolide Seems to have superior 9-month OS (secondary endpoint)

Equivalent rates of castrate testosterone levels (primary endpoint)

Endocrine therapy

28-day cycle for 9 cycles

References

  1. Heyns CF, Simonin MP, Grosgurin P, Schall R, Porchet HC; South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003 Aug;92(3):226-31. link to original article contains dosing details in manuscript PubMed

Metastatic disease, second-line hormonal therapy

Abiraterone monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Bono et al. 2011 (COU-AA-301) 2008-05 to 2009-07 Phase 3 (E-RT-esc) Prednisone Superior OS1 (primary endpoint)
Median OS: 15.8 vs 11.2 mo
(HR 0.74, 95% CI 0.64-0.86)
Ryan et al. 2013 (COU-AA-302) 2009-04 to 2010-06 Phase 3 (E-RT-esc) Prednisone Superior OS2 (co-primary endpoint)
Median OS: 34.7 vs 30.3 mo
(HR 0.81, 95% CI 0.70-0.93)
Ye et al. 2017 (ABI-PRO-3002) 2012-03-27 to 2013-02-14 Phase 3 (E-esc) Prednisone Superior TTPP (primary endpoint)
Attard et al. 2018 (PLATO) 2013-NR Phase 3 (C) Abiraterone, Enzalutamide, Prednisone Did not meet primary endpoint of PFS
Smith et al. 2019 (ERA 223) 2014-2016 Phase 3 (C) Abiraterone, Radium-223, Prednisone Did not meet primary endpoint of symptomatic skeletal EFS
Saad et al. 2021 (ACIS) 2014-2016 Phase 3 (C) Abiraterone & Apalutamide Inferior rPFS
de Wit et al. 2019 (CARD) 2015-2018 Phase 3 (C) Cabazitaxel & Prednisone Inferior PFSi/OS
Sweeney et al. 2021 (IPATential150) 2017-2019 Phase 3 (C) Abiraterone & Ipatasertib Seems to have inferior rPFS
Clarke et al. 2022 (PROpel) 2018-2020 Phase 3 (C) Abiraterone & Olaparib Might have inferior OS3
Antonarakis et al. 2023 (KEYLYNK-010) 2019-05-30 to 2021-07-16 Phase 3 (C) Olaparib & Pembrolizumab Did not meet co-primary endpoints of rPFS/OS

1Reported efficacy for COU-AA-301 is based on the 2012 update.
2Reported efficacy for COU-AA-302 is based on the 2015 update.
3Reported efficacy for PROpel is based on the 2023 update.

Prior treatment criteria

  • COU-AA-301: Chemotherapy exposure
  • COU-AA-302, ABI-PRO-3002, PLATO, ERA 223, ACIS, IPATential150: Chemotherapy naive

Preceding treatment

Endocrine therapy

Supportive therapy

28-day cycles

References

  1. COU-AA-301: de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00638690
    1. Update: Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. link to original article contains dosing details in manuscript PubMed
    2. Update: Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. link to original article contains dosing details in manuscript PubMed
  2. COU-AA-302: Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00887198
    1. Update: Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. link to original article PubMed
  3. ABI-PRO-3002: Ye D, Huang Y, Zhou F, Xie K, Matveev V, Li C, Alexeev B, Tian Y, Qiu M, Li H, Zhou T, De Porre P, Yu M, Naini V, Liang H, Wu Z, Sun Y. A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia. Asian J Urol. 2017 Apr;4(2):75-85. Epub 2017 Jan 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01591122
  4. PLATO: Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01995513
  5. ERA 223: Smith M, Parker C, Saad F, Miller K, Tombal B, Ng QS, Boegemann M, Matveev V, Piulats JM, Zucca LE, Karyakin O, Kimura G, Matsubara N, Nahas WC, Nolè F, Rosenbaum E, Heidenreich A, Kakehi Y, Zhang A, Krissel H, Teufel M, Shen J, Wagner V, Higano C. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):408-419. Epub 2019 Feb 6. link to original article contains dosing details in abstract PubMed NCT02043678
  6. CARD: de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. link to original article contains dosing details in manuscript PubMed NCT02485691
    1. HRQoL analysis: Fizazi K, Kramer G, Eymard JC, Sternberg CN, de Bono J, Castellano D, Tombal B, Wülfing C, Liontos M, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Oudard S, Facchini G, Poole EM, Ozatilgan A, Geffriaud-Ricouard C, Bensfia S, de Wit R. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020 Nov;21(11):1513-1525. Epub 2020 Sep 11. link to original article PubMed
  7. IPATential150: Sweeney C, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, Massard C, Matsubara N, Alekseev B, Parnis F, Atduev V, Buchschacher GL Jr, Gafanov R, Corrales L, Borre M, Stroyakovskiy D, Alves GV, Bournakis E, Puente J, Harle-Yge ML, Gallo J, Chen G, Hanover J, Wongchenko MJ, Garcia J, de Bono JS. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021 Jul 10;398(10295):131-142. link to original article PubMed NCT03072238
  8. ACIS: Saad F, Efstathiou E, Attard G, Flaig TW, Franke F, Goodman OB Jr, Oudard S, Steuber T, Suzuki H, Wu D, Yeruva K, De Porre P, Brookman-May S, Li S, Li J, Thomas S, Bevans KB, Mundle SD, McCarthy SA, Rathkopf DE; ACIS Investigators. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021 Nov;22(11):1541-1559. Epub 2021 Sep 30. link to original article contains dosing details in abstract link to PMC article PubMed NCT02257736
  9. PROpel: Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, Shore N, Loredo E, Procopio G, de Menezes J, Girotto G, Arslan C, Mehra N, Parnis F, Brown E, Schlürmann F, Joung JY, Sugimoto M, Virizuela JA, Emmenegger U, Navratil J, Buchschacher GL, Poehlein C, Harrington EA, Desai C, Kang J, Saad F; PROpel Investigators. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence. 2022 Sep;1(9):EVIDoa2200043. Epub 2022 Jun 3. link to original article contains dosing details in manuscript PubMed NCT03732820
    1. Update: Saad F, Clarke NW, Oya M, Shore N, Procopio G, Guedes JD, Arslan C, Mehra N, Parnis F, Brown E, Schlürmann F, Joung JY, Sugimoto M, Sartor O, Liu YZ, Poehlein C, Barker L, Del Rosario PM, Armstrong AJ. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Oct;24(10):1094-1108. Epub 2023 Sep 12. link to original article PubMed
  10. KEYLYNK-010: Antonarakis ES, Park SH, Goh JC, Shin SJ, Lee JL, Mehra N, McDermott R, Sala-Gonzalez N, Fong PC, Greil R, Retz M, Sade JP, Yanez P, Huang YH, Begbie SD, Gafanov RA, De Santis M, Rosenbaum E, Kolinsky MP, Rey F, Chiu KY, Roubaud G, Kramer G, Sumitomo M, Massari F, Suzuki H, Qiu P, Zhang J, Kim J, Poehlein CH, Yu EY. Pembrolizumab Plus Olaparib for Patients With Previously Treated and Biomarker-Unselected Metastatic Castration-Resistant Prostate Cancer: The Randomized, Open-Label, Phase III KEYLYNK-010 Trial. J Clin Oncol. 2023 Aug 1;41(22):3839-3850. Epub 2023 Jun 8. link to original article PubMed NCT03834519
  11. AMPLITUDE: NCT04497844

Abiraterone & Apalutamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Saad et al. 2021 (ACIS) 2014-2016 Phase 3 (E-esc) Abiraterone Superior rPFS (primary endpoint)
Median rPFS: 24 vs 16.6 mo
(HR 0.70, 95% CI 0.60-0.83)

Endocrine therapy

Supportive therapy

28-day cycles

References

  1. ACIS: Saad F, Efstathiou E, Attard G, Flaig TW, Franke F, Goodman OB Jr, Oudard S, Steuber T, Suzuki H, Wu D, Yeruva K, De Porre P, Brookman-May S, Li S, Li J, Thomas S, Bevans KB, Mundle SD, McCarthy SA, Rathkopf DE; ACIS Investigators. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021 Nov;22(11):1541-1559. Epub 2021 Sep 30. link to original article contains dosing details in abstract link to PMC article PubMed NCT02257736

Abiraterone & Olaparib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Clarke et al. 2022 (PROpel) 2018-2020 Phase 3 (E-RT-esc) Abiraterone Might have superior OS (secondary endpoint)
Median OS: 42.1 vs 34.7 mo
(HR 0.81, 95% CI 0.67-1.00)

Superior ibPFS (primary endpoint)
Median ibPFS: 24.8 vs 16.6 mo
(HR 0.66, 95% CI 0.54-0.81)

1Reported efficacy is based on the 2023 update.

Endocrine therapy

Targeted therapy

Supportive therapy

21-day cycle for up to 10 cycles

References

  1. PROpel: Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M, Shore N, Loredo E, Procopio G, de Menezes J, Girotto G, Arslan C, Mehra N, Parnis F, Brown E, Schlürmann F, Joung JY, Sugimoto M, Virizuela JA, Emmenegger U, Navratil J, Buchschacher GL, Poehlein C, Harrington EA, Desai C, Kang J, Saad F; PROpel Investigators. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence. 2022 Sep;1(9):EVIDoa2200043. Epub 2022 Jun 3. link to original article contains dosing details in manuscript PubMed NCT03732820
    1. Update: Saad F, Clarke NW, Oya M, Shore N, Procopio G, Guedes JD, Arslan C, Mehra N, Parnis F, Brown E, Schlürmann F, Joung JY, Sugimoto M, Sartor O, Liu YZ, Poehlein C, Barker L, Del Rosario PM, Armstrong AJ. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Oct;24(10):1094-1108. Epub 2023 Sep 12. link to original article PubMed

Antiandrogen withdrawal

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Small et al. 2004 (CALGB 9583) NR Phase 3 (C) Ketoconazole & Hydrocortisone Inferior PSA response

Refers to cessation of antiandrogen therapy.

References

  1. CALGB 9583: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. link to original article contains dosing details in manuscript PubMed NCT00002760

Apalutamide monotherapy

Regimen

Study Dates of enrollment Evidence
Rathkopf et al. 2017 (ARN-509-001) 2011-2012 Non-randomized

Endocrine therapy

Continued indefinitely

References

  1. ARN-509-001: Rathkopf DE, Antonarakis ES, Shore ND, Tutrone RF, Alumkal JJ, Ryan CJ, Saleh M, Hauke RJ, Bandekar R, Maneval EC, de Boer CJ, Yu MK, Scher HI. Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res. 2017 Jul 15;23(14):3544-3551. Epub 2017 Feb 17. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01171898

BAT

BAT: Bipolar Androgen Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Denmeade et al. 2021 (TRANSFORMER) 2015-2018 Randomized Phase 2 (E-esc) Enzalutamide Did not meet primary endpoint of PFS1
Median PFS: 5.7 vs 5.7 mo

1Study not powered for equivalency. Secondary endpoint of PFS2 after crossover was superior in BAT to enzalutamide arm.

Eligibility criteria

  • Castrate-resistant, metastatic, asymptomatic

Prior treatment criteria

  • Abiraterone, with progression

Endocrine therapy

Subsequent treatment

  • At progression, asymptomatic patients were allowed to cross over to alternative therapy

References

  1. TRANSFORMER: Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. 2021 Apr 20;39(12):1371-1382. Epub 2021 Feb 22. link to original article link to protocol link to PMC article PubMed NCT02286921

Bicalutamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shore et al. 2016 (TERRAIN) 2011-2013 Randomized Phase 2 (C) Enzalutamide Inferior PFS
Penson et al. 2016 (STRIVE) 2012-2014 Randomized Phase 2 (C) Enzalutamide Inferior PFS

Note: Patients enrollend in STRIVE continued ADT while on study; details not provided.

Prior treatment criteria

  • No prior chemotherapy, abiraterone, or ketoconazole

Endocrine therapy

Continued indefinitely

References

  1. TERRAIN: Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. Epub 2016 Jan 14. link to original article PubMed NCT01288911
  2. STRIVE: Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. link to original article contains dosing details in abstract PubMed NCT01664923

Enzalutamide monotherapy

Regimen variant #1, 160 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Scher et al. 2012 (AFFIRM) 2009-09 to 2010-11 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 18.4 vs 13.6 mo
(HR 0.63, 95% CI 0.53-0.75)
Beer et al. 2014 (PREVAIL) 2010-2012 Phase 3 (E-RT-esc) Placebo Superior rPFS1 (co-primary endpoint)
Median rPFS: 20 vs 5.4 mo
(HR 0.32, 95% CI 0.28-0.37)

Superior OS2 (co-primary endpoint)
Median OS: 36 vs 31 mo
(HR 0.83, 95% CI 0.75-0.93)
Shore et al. 2016 (TERRAIN) 2011-2013 Randomized Phase 2 (E-RT-switch-ic) Bicalutamide Superior PFS (primary endpoint)
Median PFS: 15.7 vs 5.8 mo
(HR 0.44, 95% CI 0.34-0.57)
Penson et al. 2016 (STRIVE) 2012-2014 Randomized Phase 2 (E-switch-ic) Bicalutamide Superior PFS (primary endpoint)
Median PFS: 19.4 vs 5.7 mo
(HR 0.24, 95% CI 0.18-0.32)
Attard et al. 2018 (PLATO) 2013-NR Non-randomized part of phase 3 RCT
Morris et al. 2023 (Alliance A031201) 2014-01-28 to 2016-08-31 Phase 3 (C) Abiraterone & Enzalutamide Might have inferior OS (primary endpoint)
Median OS: 32.7 vs 34.2 mo
(HR 1.12, 95% CI 0.99-1.28)
Pu et al. 2022 (9785-CL-0232) 2014-04-23 to 2015-09-20 Phase 3 (E-esc) Placebo Superior OS (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.33, 95% CI 0.16-0.67)

Superior time to PSA progression (primary endpoint)
Median time to PSA progression: 8.31 vs 2.86 mo
(HR 0.38, 95% CI 0.27-0.52)
de Wit et al. 2019 (CARD) 2015-2018 Phase 3 (C) Cabazitaxel & Prednisone Inferior PFSi/OS
Denmeade et al. 2021 (TRANSFORMER) 2015-2018 Randomized Phase 2 (C) Bipolar androgen therapy Did not meet primary endpoint of PFS
Powles et al. 2022 (IMbassador250) 2017-06 to 2018-05 Phase 3 (C) Enzalutamide & Atezolizumab Did not meet primary endpoint of OS
Antonarakis et al. 2023 (KEYLYNK-010) 2019-05-30 to 2021-07-16 Phase 3 (C) Olaparib & Pembrolizumab Did not meet co-primary endpoints of rPFS/OS

1Reported efficacy for rPFS in PREVAIL is based on the 2016 update.
1Reported efficacy for OS in PREVAIL is based on the 2020 update.
Note: Patients in STRIVE, PLATO, & TRANSFORMER continued ADT while on study or had a history of bilateral orchiectomy; details not provided.

Prior treatment criteria

  • AFFIRM: Exposure to docetaxel
  • PREVAIL: Chemotherapy and abiraterone naive
  • STRIVE: Chemotherapy and bicalutamide naive
  • PLATO & 9785-CL-0232: Chemotherapy naive
  • TRANSFORMER: Exposure to abiraterone

Endocrine therapy

Continued indefinitely

Subsequent treatment

  • PLATO, with rising PSA: Abiraterone versus Abiraterone & Enzalutamide
  • TRANSFORMER, asymptomatic PSA or radiographic progression: crossover to alternative arm. Secondary endpoint of PFS2 was statistically longer with BAT to Enzalutamide compared to Enzalutamide to BAT


Regimen variant #2, 240 mg/day

Historic variant
Study Dates of enrollment Evidence
Scher et al. 2010 (S-3100-1-01) 2007-2008 Phase 1/2

Note: this is the reported MTD from the phase 1 portion of the trial; however, it is NOT the dose used in subsequent phase 3 studies.

Endocrine therapy

Continued indefinitely

References

  1. S-3100-1-01: Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL; Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. Epub 2010 Apr 14. link to original article link to PMC article contains dosing details in abstract PubMed NCT00510718
  2. AFFIRM: Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97. Epub 2012 Aug 15. link to original article contains dosing details in manuscript PubMed NCT00974311
  3. PREVAIL: Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1. link to original article link to PMC article PubMed NCT01212991
    1. HRQoL analysis: Loriot Y, Miller K, Sternberg CN, Fizazi K, De Bono JS, Chowdhury S, Higano CS, Noonberg S, Holmstrom S, Mansbach H, Perabo FG, Phung D, Ivanescu C, Skaltsa K, Beer TM, Tombal B. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol. 2015 May;16(5):509-21. Epub 2015 Apr 14. link to original article PubMed
    2. Update: Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, Evans CP, Kim CS, Kimura G, Miller K, Saad F, Bjartell AS, Borre M, Mulders P, Tammela TL, Parli T, Sari S, van Os S, Theeuwes A, Tombal B. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: Extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017 Feb;71(2):151-154. Epub 2016 Jul 28. link to original article link to PMC article PubMed
    3. HRQoL analysis: Devlin N, Herdman M, Pavesi M, Phung D, Naidoo S, Beer TM, Tombal B, Loriot Y, Ivanescu C, Parli T, Balk M, Holmstrom S. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Health Qual Life Outcomes. 2017 Jun 23;15(1):130. link to original article link to PMC article PubMed
    4. Update: Armstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, Parli T, Rosbrook B, van Os S, Beer TM. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol. 2020 Sep;78(3):347-357. Epub 2020 Jun 9. link to original article PubMed
  4. TERRAIN: Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, van Os S, Hasabou N, Wang F, Bhattacharya S, Heidenreich A. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-163. Epub 2016 Jan 14. link to original article PubMed NCT01288911
  5. STRIVE: Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, Dunshee C, Wang F, Wu K, Krivoshik A, Phung D, Higano CS. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jun 20;34(18):2098-106. Epub 2016 Jan 25. link to original article contains dosing details in abstract PubMed NCT01664923
  6. PLATO: Attard G, Borre M, Gurney H, Loriot Y, Andresen-Daniil C, Kalleda R, Pham T, Taplin ME; PLATO collaborators. Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment. J Clin Oncol. 2018 Sep 1;36(25):2639-2646. Epub 2018 Jul 20. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01995513
  7. CARD: de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. link to original article contains dosing details in manuscript PubMed NCT02485691
    1. HRQoL analysis: Fizazi K, Kramer G, Eymard JC, Sternberg CN, de Bono J, Castellano D, Tombal B, Wülfing C, Liontos M, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Oudard S, Facchini G, Poole EM, Ozatilgan A, Geffriaud-Ricouard C, Bensfia S, de Wit R. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020 Nov;21(11):1513-1525. Epub 2020 Sep 11. link to original article PubMed
  8. TRANSFORMER: Denmeade SR, Wang H, Agarwal N, Smith D, Schweizer MT, Stein MN, Assikis V, Twardowski P, Flaig T, Szmulewitz R, Holzbeierlein J, Hauke R, Sonpavde G, Garcia J, Hussain A, Sartor O, Mao S, Cao H, Fu W, Wang T, Abdallah R, Lim SJ, Bolejack V, Paller C, Carducci M, Markowski MC, Eisenberger MA, Antonarakis ES; TRANSFORMER investigators. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Prostate Cancer. J Clin Oncol. 2021 Apr 20;39(12):1371-1382. Epub 2021 Feb 22. link to original article link to protocol link to PMC article PubMed NCT02286921
  9. IMbassador250: Powles T, Yuen KC, Gillessen S, Kadel EE 3rd, Rathkopf D, Matsubara N, Drake CG, Fizazi K, Piulats JM, Wysocki PJ, Buchschacher GL Jr, Alekseev B, Mellado B, Karaszewska B, Doss JF, Rasuo G, Datye A, Mariathasan S, Williams P, Sweeney CJ. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022 Jan;28(1):144-153. Epub 2022 Jan 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT03016312
  10. 9785-CL-0232: Pu YS, Ahn H, Han W, Huang SP, Wu HC, Ma L, Yamada S, Suga K, Xie LP. Enzalutamide in Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Asian Multiregional, Randomized Study. Adv Ther. 2022 Jun;39(6):2641-2656. Epub 2022 Apr 10. link to original article contains dosing details in abstract link to PMC article PubMed NCT02294461
  11. KEYLYNK-010: Antonarakis ES, Park SH, Goh JC, Shin SJ, Lee JL, Mehra N, McDermott R, Sala-Gonzalez N, Fong PC, Greil R, Retz M, Sade JP, Yanez P, Huang YH, Begbie SD, Gafanov RA, De Santis M, Rosenbaum E, Kolinsky MP, Rey F, Chiu KY, Roubaud G, Kramer G, Sumitomo M, Massari F, Suzuki H, Qiu P, Zhang J, Kim J, Poehlein CH, Yu EY. Pembrolizumab Plus Olaparib for Patients With Previously Treated and Biomarker-Unselected Metastatic Castration-Resistant Prostate Cancer: The Randomized, Open-Label, Phase III KEYLYNK-010 Trial. J Clin Oncol. 2023 Aug 1;41(22):3839-3850. Epub 2023 Jun 8. link to original article PubMed NCT03834519
  12. Alliance A031201: Morris MJ, Heller G, Hillman DW, Bobek O, Ryan C, Antonarakis ES, Bryce AH, Hahn O, Beltran H, Armstrong AJ, Schwartz L, Lewis LD, Beumer JH, Langevin B, McGary EC, Mehan PT, Goldkorn A, Roth BJ, Xiao H, Watt C, Taplin ME, Halabi S, Small EJ. Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial). J Clin Oncol. 2023 Jun 20;41(18):3352-3362. Epub 2023 Mar 30. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01949337
  13. CASPAR: NCT04455750
  14. TALAPRO-2: NCT03395197

Hydrocortisone monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kantoff et al. 1999 (CALGB 9182) 1992-1995 Phase 3 (C) Mitoxantrone & Hydrocortisone Did not meet primary endpoint of OS
Small et al. 2000 1994-1996 Phase 3 (C) Suramin & Hydrocortisone Inferior TTP
Abratt et al. 2004 1997-2001 Phase 3 (C) Vinorelbine & Hydrocortisone Might have inferior PFS

Endocrine therapy

Continued indefinitely

References

  1. CALGB 9182: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. link to original article contains dosing details in manuscript PubMed
  2. Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, Lenehan PF, Chen L, Slichenmyer WJ, Eisenberger M. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol. 2000 Apr;18(7):1440-50. link to original article PubMed
  3. Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, Beuzeboc P, Demkow T, Oudard S. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol. 2004 Nov;15(11):1613-21. link to original article PubMed

Ketoconazole & Hydrocortisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Trachtenberg & Pont 1984 NR Pilot
Small et al. 2004 (CALGB 9583) NR Phase 3 (E-esc) Antiandrogen withdrawal Superior PSA response

Endocrine therapy

Continued indefinitely

References

  1. Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 1984 Aug 25;2(8400):433-5. link to original article PubMed
  2. CALGB 9583: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. link to original article contains dosing details in manuscript PubMed NCT00002760

Ketoconazole, Hydrocortisone, Dutasteride

Regimen

Study Dates of enrollment Evidence
Taplin et al. 2009 2005-2007 Phase 2

Endocrine therapy

Continued indefinitely

References

  1. Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L, Beer TM, Ryan CW, Mathew P, Tu SM, Denmeade SR, Oh WK, Sartor O, Mantzoros CS, Rittmaster R, Kantoff PW, Balk SP. Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009 Nov 15;15(22):7099-105. Epub 2009 Nov 3. link to original article contains dosing details in manuscript link to PMC article PubMed

Prednisone monotherapy

Regimen variant #1, 5 mg twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tannock et al. 1989 1976-1980 Retrospective
Tannock et al. 1996 (CCI-NOV22) 1990-1994 Phase 3 (C) Mitoxantrone & Prednisone Inferior palliation
Berry et al. 2002 1997-1999 Phase 3 (C) Mitoxantrone & Prednisone Seems to have inferior TTTF
Sternberg et al. 2009 (SPARC) 2003-2006 Phase 3 (C) Satraplatin & Prednisone Inferior PFS
de Bono et al. 2011 (COU-AA-301) 2008-05 to 2009-07 Phase 3 (C) Abiraterone Inferior OS
Michaelson et al. 2013 (SUN 1120) 2008-2010 Phase 3 (C) Sunitinib & Prednisone Did not meet primary endpoint of OS
Ryan et al. 2013 (COU-AA-302) 2009-04 to 2010-06 Phase 3 (C) Abiraterone Inferior OS
Saad et al. 2015 (ELM-PC 4) 2010-2012 Phase 3 (C) Orteronel & Prednisone Inferior PFS
Fizazi et al. 2015 (ELM-PC 5) 2010-NR Phase 3 (C) Orteronel & Prednisone Did not meet primary endpoint of OS
Smith et al. 2016 (COMET-1) 2012-2014 Phase 3 (C) Cabozantinib Did not meet primary endpoint of OS

Endocrine therapy

Continued indefinitely


Regimen variant #2, 5 mg QID

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fosså et al. 2001 (EORTC 30903) 1992-1998 Phase 3 (C) Flutamide Did not meet co-primary endpoints of TTP/OS

Endocrine therapy

Continued indefinitely

References

  1. Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol. 1989 May;7(5):590-7. link to original article PubMed
  2. CCI-NOV22: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. link to original article contains dosing details in manuscript PubMed
    1. HRQoL analysis: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. link to original article PubMed
  3. EORTC 30903: Fosså SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, Aaronson N, de Prijck L, Collette L. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol. 2001 Jan 1;19(1):62-71. link to original article contains dosing details in abstract PubMed
  4. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. link to original article contains dosing details in abstract PubMed
  5. SPARC: Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabrò F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009 Nov 10;27(32):5431-8. Epub 2009 Oct 5. link to original article contains dosing details in abstract PubMed NCT00069745
  6. COU-AA-301: de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00638690
    1. Update: Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS; COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13(10):983-92. Epub 2012 Sep 18. link to original article contains dosing details in manuscript PubMed
    2. Update: Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, Efstathiou E, Gagnon DD, Rothman M, Hao Y, Liu CS, Kheoh TS, Haqq CM, Scher HI, de Bono JS. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012 Dec;13(12):1210-7. Epub 2012 Nov 9. link to original article contains dosing details in manuscript PubMed
  7. COU-AA-302: Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. Epub 2012 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00887198
    1. Update: Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. Epub 2015 Jan 16. link to original article PubMed
  8. SUN 1120: Michaelson MD, Oudard S, Ou YC, Sengeløv L, Saad F, Houede N, Ostler P, Stenzl A, Daugaard G, Jones R, Laestadius F, Ullèn A, Bahl A, Castellano D, Gschwend J, Maurina T, Chow Maneval E, Wang SL, Lechuga MJ, Paolini J, Chen I. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol. 2014 Jan 10;32(2):76-82. Epub 2013 Dec 9. link to original article contains dosing details in abstract PubMed NCT00676650
  9. ELM-PC 5: Fizazi K, Jones R, Oudard S, Efstathiou E, Saad F, de Wit R, De Bono J, Cruz FM, Fountzilas G, Ulys A, Carcano F, Agarwal N, Agus D, Bellmunt J, Petrylak DP, Lee SY, Webb IJ, Tejura B, Borgstein N, Dreicer R. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. 2015 Mar 1;33(7):723-31. Epub 2015 Jan 26. link to original article link to PMC article contains dosing details in abstract PubMed NCT01193257
  10. ELM-PC 4: Saad F, Fizazi K, Jinga V, Efstathiou E, Fong PC, Hart LL, Jones R, McDermott R, Wirth M, Suzuki K, MacLean DB, Wang L, Akaza H, Nelson J, Scher HI, Dreicer R, Webb IJ, de Wit R; ELM-PC 4 investigators. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial. Lancet Oncol. 2015 Mar;16(3):338-48. Epub 2015 Feb 18. link to original article contains dosing details in abstract PubMed NCT01193244
  11. COMET-1: Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. link to original article contains dosing details in manuscript PubMed NCT01605227

Chemotherapy for metastatic castrate-sensitive disease

Cabazitaxel & Prednisone

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Wit et al. 2019 (CARD) 2015-2018 Phase 3 (E-RT-switch-ooc) 1a. Abiraterone
1b. Enzalutamide 		Superior PFSi (primary endpoint)
Median PFSi: 8 vs 3.7 mo
(HR 0.54, 95% CI 0.40-0.73)

Superior OS (secondary endpoint)
Median OS: 13.6 vs 11 mo
(HR 0.64, 95% CI 0.46-0.89)

Note: patients in CARD had already received and progressed on the alternate androgen signaling targeted inhibitor.

Chemotherapy

Endocrine therapy

Supportive therapy

21-day cycles

References

  1. CARD: de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Kramer G, Eymard JC, Bamias A, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Ozatilgan A, Geffriaud-Ricouard C, Castellano D; CARD Investigators. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019 Dec 26;381(26):2506-2518. Epub 2019 Sep 30. link to original article contains dosing details in manuscript PubMed NCT02485691
    1. HRQoL analysis: Fizazi K, Kramer G, Eymard JC, Sternberg CN, de Bono J, Castellano D, Tombal B, Wülfing C, Liontos M, Carles J, Iacovelli R, Melichar B, Sverrisdóttir Á, Theodore C, Feyerabend S, Helissey C, Oudard S, Facchini G, Poole EM, Ozatilgan A, Geffriaud-Ricouard C, Bensfia S, de Wit R. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020 Nov;21(11):1513-1525. Epub 2020 Sep 11. link to original article PubMed

Chemotherapy for metastatic castrate-resistant disease

Cabazitaxel & Prednisolone

Example orders

Regimen variant #1, 16/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Oudard et al. 2023 (CABASTY) NR Phase 3 (E-de-esc) Cabazitaxel & Prednisone; q3wk Superior grade 3 or higher neutropenia and/or neutropenic complications (primary endpoint)

Chemotherapy

Endocrine therapy

Supportive therapy

  • G-CSF (dose not specified) once per day on days 3 to 7

14-day cycle for up to 20 cycles


Regimen variant #2, 20/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hofman et al. 2021 (TheraP) 2018-2019 Randomized Phase 2 (C) Lu-177 Lu-PSMA-617 Inferior PSA response

Chemotherapy

Endocrine therapy

21-day cycle for up to 10 cycles


Regimen variant #3, 25/10

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Oudard et al. 2023 (CABASTY) NR Phase 3 (C) Cabazitaxel & Prednisone; q2wk Inferior grade 3 or higher neutropenia and/or neutropenic complications

Chemotherapy

Endocrine therapy

Supportive therapy

  • G-CSF (dose not specified) once per day on days 3 to 7

21-day cycle for up to 10 cycles

References

  1. TheraP: Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, McJannett MM, Stockler MR, Violet JA, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804. Epub 2021 Feb 11. link to original article contains dosing details in abstract PubMed NCT03392428
    1. Update: Hofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, Stockler MR, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024 Jan;25(1):99-107. Epub 2023 Nov 30. link to original article PubMed
  2. CABASTY: Oudard S, Ratta R, Voog E, Barthelemy P, Thiery-Vuillemin A, Bennamoun M, Hasbini A, Aldabbagh K, Saldana C, Sevin E, Amela E, Von Amsberg G, Houede N, Besson D, Feyerabend S, Boegemann M, Pfister D, Schostak M, Huillard O, Di Fiore F, Quivy A, Lange C, Phan L, Belhouari H, Tran Y, Kotti S, Helissey C. Biweekly vs Triweekly Cabazitaxel in Older Patients With Metastatic Castration-Resistant Prostate Cancer: The CABASTY Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023 Dec 1;9(12):1629-1638. Epub 2023 Oct 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02961257

Cabazitaxel & Prednisone

Example orders

Regimen variant #1, 20/10, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oudard et al. 2017 (FIRSTANA) 2011-2013 Phase 3 (E-switch-ic) 1. Cabazitaxel & Prednisone; 25 mg/m2/10 mg Did not meet primary endpoint of OS
2. Docetaxel & Prednisone Did not meet primary endpoint of OS
Eisenberger et al. 2017 (PROSELICA) 2011-2013 Phase 3 (E-RT-de-esc) Cabazitaxel & Prednisone; 25 mg/m2/10 mg Non-inferior OS (primary endpoint)
Median OS: 13.4 vs 14.5 mo
(HR 1.024, 98.89% CI 1.184)

Chemotherapy

Endocrine therapy

21-day cycles


Regimen variant #2, 25/10 x 10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
de Bono et al. 2010 (TROPIC) 2007-01-02 to 2008-10-23 Phase 3 (E-RT-switch-ic) Mitoxantrone & Prednisone Superior OS (primary endpoint)
Median OS: 15.1 vs 12.7 mo
(HR 0.70, 95% CI 0.59-0.83)
Beer et al. 2017 (AFFINITY) 2012-2014 Phase 3 (C) Cabazitaxel, Prednisone, Custirsen Did not meet primary endpoint of OS

1ORRs in TROPIC were only reported for patients with measurable disease.

Prior treatment criteria

  • TROPIC: Previous endocrine therapy, and failure of a docetaxel-containing regimen
  • AFFINITY: Castration-resistant prostate cancer and failure of a docetaxel-containing regimen

Chemotherapy

Endocrine therapy

Supportive therapy

21-day cycle for up to 10 cycles


Regimen variant #3, 25/10, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oudard et al. 2017 (FIRSTANA) 2011-2013 Phase 3 (E-switch-ic) 1. Cabazitaxel & Prednisone; 20 mg/m2/10 mg Did not meet primary endpoint of OS
2. Docetaxel & Prednisone Did not meet primary endpoint of OS
Eisenberger et al. 2017 (PROSELICA) 2011-2013 Phase 3 (C) Cabazitaxel & Prednisone; 20 mg/m2/10 mg Non-inferior OS

Chemotherapy

Endocrine therapy

Supportive therapy

21-day cycles

References

  1. TROPIC: de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. link to original article contains dosing details in manuscript PubMed NCT00417079
  2. FIRSTANA: Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. link to original article contains dosing details in manuscript PubMed NCT01308567
  3. PROSELICA: Eisenberger M, Hardy-Bessard AC, Kim CS, Géczi L, Ford D, Mourey L, Carles J, Parente P, Font A, Kacso G, Chadjaa M, Zhang W, Bernard J, de Bono J. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m(2)) and the currently approved dose (25 mg/m(2)) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017 Oct 1;35(28):3198-3206. Epub 2017 Aug 15 link to original article contains dosing details in supplement PubMed NCT01308580
  4. AFFINITY: Beer TM, Hotte SJ, Saad F, Alekseev B, Matveev V, Fléchon A, Gravis G, Joly F, Chi KN, Malik Z, Blumenstein B, Stewart PS, Jacobs CA, Fizazi K. Custirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1532-1542. Epub 2017 Oct 9. link to original article PubMed NCT01578655

Cabozantinib monotherapy

Regimen variant #1, 60 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2016 (COMET-1) 2012-2014 Phase 3 (E-switch-ooc) Prednisone Did not meet primary endpoint of OS

Targeted therapy

28-day cycles


Regimen variant #2, 100 mg/day

Study Dates of enrollment Evidence
Smith et al. 2012 (XL184-203) 2009-2011 Phase 2

Targeted therapy

Continued indefinitely

References

  1. XL184-203: Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013 Feb 1;31(4):412-9. Epub 2012 Nov 19. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00940225
  2. COMET-1: Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bögemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houédé N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016 Sep 1;34(25):3005-13. Epub 2016 Jul 11. link to original article contains dosing details in manuscript PubMed NCT01605227

Carboplatin & Docetaxel

Example orders

Regimen

Study Dates of enrollment Evidence
Ross et al. 2008 2004-2006 Phase 2

Eligibility criteria

  • Hormone-refractory prostate cancer and progression of disease during docetaxel treatment or within 45 days of stopping docetaxel treatment

Chemotherapy

Supportive therapy

  • "Standard dexamethasone premedication was used"
  • Patients continued to receive androgen deprivation therapy

21-day cycles

References

  1. Ross RW, Beer TM, Jacobus S, Bubley GJ, Taplin ME, Ryan CW, Huang J, Oh WK; Prostate Cancer Clinical Trials Consortium. A phase 2 study of carboplatin plus docetaxel in men with metastatic hormone-refractory prostate cancer who are refractory to docetaxel. Cancer. 2008 Feb 1;112(3):521-6. link to original article contains dosing details in manuscript PubMed
  2. Retrospective: Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int. 2008 Feb;101(3):308-12. link to original article PubMed

Carboplatin, Docetaxel, Prednisone

Regimen

Study Dates of enrollment Evidence
Reuter et al. 2010 2005-NR Phase 2

Prior treatment criteria

  • Docetaxel exposure with progression and castration-resistant disease

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1
  • Docetaxel (Taxotere) 35 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
    • Note: In contrast to its abstract, Reuter et al. 2010 sometimes used "days 1, 8, (15)" to describe when docetaxel was given. The paper did not specifically say what "(15)" meant, such as whether this meant that the day 15 dose was optional.

Endocrine therapy

Supportive therapy

  • "Standard dexamethasone premedication was used"
  • Patients continued to receive LHRH (luteinizing hormone releasing hormone) agonists
  • No routine use of granulocyte colony-stimulating factor (G-CSF)

28-day cycles

References

  1. Reuter CW, Morgan MA, Ivanyi P, Fenner M, Ganser A, Grünwald V. Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 2010 Jun;28(3):391-8. Epub 2010 Mar 14. link to original article contains dosing details in manuscript PubMed

Carboplatin & Paclitaxel (CP)

Regimen variant #1

Study Dates of enrollment Evidence
Kentepozidis et al. 2012 2006-2009 Phase 2

Chemotherapy

Supportive therapy

  • "All patients received a concomitant anti-emetic prophylaxis"
  • Dexamethasone (Decadron) 20 mg PO given twice, 12 and 6 hours prior to paclitaxel
  • Diphenhydramine (Benadryl) 50 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of paclitaxel)
  • Cimetidine (Tagamet) 300 mg IV once per day on days 1 & 15, "prior to each dose" (there was nothing else after this in Kentepozidis et al. 2012, and it is assumed to mean prior to each dose of paclitaxel)
  • No prophylactic G-CSF

28-day cycles


Regimen variant #2

Study Evidence
Jeske et al. 2010 Retrospective

Chemotherapy

28-day cycles

References

  1. Retrospective: Jeske S, Tagawa ST, Olowokure O, Selzer J, Giannakakou P, Nanus DM. Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer. Urol Oncol. 2011 Nov-Dec;29(6):676-81. Epub 2010 May 7. link to original article contains dosing details in manuscript PubMed
  2. Kentepozidis N, Soultati A, Giassas S, Vardakis N, Kalykaki A, Kotsakis A, Papadimitraki E, Pantazopoulos N, Bozionellou V, Georgoulias V; Hellenic Oncology Research Group. Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic Oncology Research Group multicenter phase II study. Cancer Chemother Pharmacol. 2012 Jul;70(1):161-8. Epub 2012 Jun 3. link to original article contains dosing details in manuscript PubMed

Docetaxel, Enzalutamide, Prednisolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Merseburger et al. 2022 (PRESIDE) 2014-2016 Phase 3 (E-esc) Docetaxel & Prednisolone Seems to have superior PFS (primary endpoint)
Median PFS: 9.5 vs 8.3 mo
(HR 0.72, 95% CI 0.53-0.96)

Chemotherapy

Endocrine therapy

21-day cycle for up to 10 cycles

References

  1. PRESIDE: Merseburger AS, Attard G, Åström L, Matveev VB, Bracarda S, Esen A, Feyerabend S, Senkus E, López-Brea Piqueras M, Boysen G, Gourgioti G, Martins K, Chowdhury S. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol. 2022 Nov;23(11):1398-1408. Epub 2022 Oct 18. link to original article contains dosing details in abstract PubMed NCT02288247

Docetaxel & Estramustine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Petrylak et al. 2004 (SWOG S9916) 1999-2003 Phase 3 (E-switch-ic) Mitoxantrone & Prednisone Seems to have superior OS (primary endpoint)
Median OS: 17.5 vs 15.6 mo
(HR 0.80, 95% CI 0.67-0.97)

Prior treatment criteria

  • SWOG S9916: Hormone-independent prostate cancer

Chemotherapy

21-day cycles

References

  1. SWOG S9916: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. link to original article contains dosing details in abstract PubMed NCT00004001
  2. ECOG E1899: NCT00027859

Docetaxel & Prednisone

Example orders

Regimen variant #1, 30 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tannock et al. 2004 (TAX 327) 2000-2002 Phase 3 (E-RT-switch-ic) 1. Docetaxel & Prednisone; q3wk Not reported
2. Mitoxantrone & Prednisone Did not meet primary endpoint of OS
Median OS: 17.4 vs 16.5 mo
(HR 0.91, 95% CI 0.75-1.11)

Prior treatment criteria

  • TAX 327: Disease progression during hormonal therapy

Chemotherapy

Endocrine therapy

Supportive therapy

  • Dexamethasone (Decadron) 8 mg (route not specified) once 1 hour prior to docetaxel
  • Antiemetics "according to local practice"

42-day cycle for up to 5 cycles


Regimen variant #2, 75 mg/m2 q3wk x 10

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tannock et al. 2004 (TAX 327) 2000-2002 Phase 3 (E-RT-switch-ic) 1. Docetaxel & Prednisone; weekly Not reported
2. Mitoxantrone & Prednisone Superior OS (primary endpoint)
Median OS: 18.9 vs 16.5 mo
(HR 0.76, 95% CI 0.62-0.94)
Beer et al. 2011 (ASCENTPRCA) 2002-2004 Phase 3 (C) Calcitriol, Docetaxel, Prednisone Superior OS1
Meulenbeld et al. 2012 (NePro) 2004-2010 Phase 2/3 (C) Docetaxel, Prednisone, Risedronate Did not meet primary endpoint of TTP
Zhou et al. 2015 (DOCET_L_01833) 2007-2010 Phase 3 (E-switch-ic) Mitoxantrone & Prednisone Superior OS (primary endpoint)
Median OS: 21.9 vs 13.7 mo
(HR 0.63, 95% CI 0.46-0.86)
Vogelzang et al. 2022 (VIABLE) 2014-2017 Phase 3 (C) Docetaxel, Prednisone, DCVAC/PCa Did not meet primary endpoint of OS

1Reported efficacy for ASCENT is based on the 2011 update.
Note: ASCENT is labeled ASCENTPRCA to distinguish from the trial by the same name in TNBC.

Prior treatment criteria

  • TAX 327: Disease progression during hormonal therapy

Chemotherapy

Endocrine therapy

Supportive therapy

21-day cycle for up to 10 cycles


Regimen variant #3, 75 mg/m2 q3wk x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Quinn et al. 2013 (SWOG S0421) 2006-2010 Phase 3 (C) Atrasentan, Docetaxel, Prednisone Did not meet co-primary endpoints of PFS/OS

Chemotherapy

Endocrine therapy

Supportive therapy

21-day cycle for up to 12 cycles


Regimen variant #4, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kelly et al. 2012 (CALGB 90401) 2005-2007 Phase 3 (C) Docetaxel, Prednisone, Bevacizumab Did not meet primary endpoint of OS
Tannock et al. 2013 (VENICE) 2007-2010 Phase 3 (C) Aflibercept, Docetaxel, Prednisone Did not meet primary endpoint of OS
Araujo et al. 2013 (READY) 2008-2011 Phase 3 (C) Dasatinib, Docetaxel, Prednisone Did not meet primary endpoint of OS
Fizazi et al. 2013 (ENTHUSE) 2008-NR Phase 3 (C) 1a. Docetaxel, Prednisolone, Zibotentan
1b. Docetaxel, Prednisone, Zibotentan 		Did not meet primary endpoint of OS
Petrylak et al. 2015 (MAINSAIL) 2009-2011 Phase 3 (C) Docetaxel, Lenalidomide, Prednisone Superior OS
Chi et al. 2017 (SYNERGY) 2010-2012 Phase 3 (C) Custirsen, Docetaxel, Prednisone Did not meet primary endpoint of OS
Oudard et al. 2017 (FIRSTANA) 2011-2013 Phase 3 (C) 1. Cabazitaxel & Prednisone; 20 mg/m2/10 mg Did not meet primary endpoint of OS
2. Cabazitaxel & Prednisone; 25 mg/m2/10 mg Did not meet primary endpoint of OS

Note: patients in CALGB 90401 discontinued treatment after a maximum of 2 years.

Chemotherapy

Endocrine therapy

  • Prednisone (Sterapred) by the following study-specific criteria:
    • CALGB 90401: 5 mg PO once per day on days 1 to 21
    • Others: 10 mg/day; some regimens give as 5 mg PO twice per day, some as 10 mg PO once per day

21-day cycles

References

  1. TAX 327: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. link to original article contains dosing details in manuscript PubMed
    1. Update: Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. link to original article contains dosing details in manuscript PubMed
  2. ASCENTPRCA: Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW; ASCENT Investigators. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74. link to original article PubMed NCT00273338
    1. Update: Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, Henick B, Waterhouse D, Ruether DJ, Rosen PJ, Meluch AA, Nordquist LT, Venner PM, Heidenreich A, Chu L, Heller G. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011 Jun 1;29(16):2191-8. Epub 2011 Apr 11. link to original article PubMed
  3. CALGB 90401: Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012 May 1;30(13):1534-40. Epub 2012 Mar 26. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00110214
  4. NePro: Meulenbeld HJ, van Werkhoven ED, Coenen JL, Creemers GJ, Loosveld OJ, de Jong PC, Ten Tije AJ, Fosså SD, Polee M, Gerritsen W, Dalesio O, de Wit R. Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro). Eur J Cancer. 2012 Nov;48(16):2993-3000. Epub 2012 Jun 6. link to original article contains dosing details in manuscript PubMed
  5. VENICE: Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Arén O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. Epub 2013 Jun 4. link to original article contains dosing details in abstract PubMed NCT00519285
  6. SWOG S0421: Quinn DI, Tangen CM, Hussain M, Lara PN Jr, Goldkorn A, Moinpour CM, Garzotto MG, Mack PC, Carducci MA, Monk JP, Twardowski PW, Van Veldhuizen PJ, Agarwal N, Higano CS, Vogelzang NJ, Thompson IM Jr. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013 Aug;14(9):893-900. Epub 2013 Jul 17. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00134056
  7. READY: Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, Efstathiou E, Oudard S, Morris MJ, Sizer B, Goebell PJ, Heidenreich A, de Bono JS, Begbie S, Hong JH, Richardet E, Gallardo E, Paliwal P, Durham S, Cheng S, Logothetis CJ. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1307-16. Epub 2013 Nov 8. link to original article contains dosing details in abstract link to PMC article PubMed NCT00744497
  8. DOCET_L_01833: Zhou T, Zeng SX, Ye DW, Wei Q, Zhang X, Huang YR, Ye ZQ, Yang Y, Zhang W, Tian Y, Zhou FJ, Jie J, Chen SP, Sun Y, Xie LP, Yao X, Na YQ, Sun YH. A multicenter, randomized clinical trial comparing the three-weekly docetaxel regimen plus prednisone versus mitoxantone plus prednisone for Chinese patients with metastatic castration refractory prostate cancer. PLoS One. 2015 Jan 27;10(1):e0117002. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00436839
  9. MAINSAIL: Petrylak DP, Vogelzang NJ, Budnik N, Wiechno PJ, Sternberg CN, Doner K, Bellmunt J, Burke JM, de Olza MO, Choudhury A, Gschwend JE, Kopyltsov E, Flechon A, Van As N, Houede N, Barton D, Fandi A, Jungnelius U, Li S, de Wit R, Fizazi K. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2015 Apr;16(4):417-25. Epub 2015 Mar 3. link to original article contains dosing details in abstract PubMed NCT00988208
  10. SYNERGY: Chi KN, Higano CS, Blumenstein B, Ferrero JM, Reeves J, Feyerabend S, Gravis G, Merseburger AS, Stenzl A, Bergman AM, Mukherjee SD, Zalewski P, Saad F, Jacobs C, Gleave M, de Bono JS. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2017 Apr;18(4):473-485. Epub 2017 Mar 8. link to original article contains dosing details in abstract PubMed NCT01188187
  11. FIRSTANA: Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, Hjälm-Eriksson M, Jassem J, Thiery-Vuillemin A, Caffo O, Castellano D, Mainwaring PN, Bernard J, Shen L, Chadjaa M, Sartor O. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: A randomized phase III Trial-FIRSTANA. J Clin Oncol. 2017 Oct 1;35(28):3189-3197. Epub 2017 Jul 28. link to original article contains dosing details in manuscript PubMed NCT01308567
  12. Bianchi S, Mosca A, Dalla Volta A, Prati V, Ortega C, Buttigliero C, Fea E, Vanella P, Valcamonico F, Zamparini M, Sirotova Z, Chiappino I, Dal Canton O, Masini C, Sacco C, Amoroso D, Montagnani F, Comandone A, Bellissimo AR, Ciccone G, Baier S, Gennari A, Tucci M, Berruti A. Maintenance versus discontinuation of androgen deprivation therapy during continuous or intermittent docetaxel administration in castration-resistant prostate cancer patients: A multicentre, randomised Phase III study by the Piemonte Oncology Network. Eur J Cancer. 2021 Sep;155:127-135. Epub 2021 Aug 6. link to original article PubMed
  13. VIABLE: Vogelzang NJ, Beer TM, Gerritsen W, Oudard S, Wiechno P, Kukielka-Budny B, Samal V, Hajek J, Feyerabend S, Khoo V, Stenzl A, Csöszi T, Filipovic Z, Goncalves F, Prokhorov A, Cheung E, Hussain A, Sousa N, Bahl A, Hussain S, Fricke H, Kadlecova P, Scheiner T, Korolkiewicz RP, Bartunkova J, Spisek R; VIABLE Investigators. Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial. JAMA Oncol. 2022 Apr 1;8(4):546-552. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02111577
  14. DORA: NCT03574571

Docetaxel & Prednisolone

Example orders

Regimen variant #1, 50 mg/m2 bi-weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY) 2004-2009 Phase 3 (E-switch-ic) Docetaxel & Prednisolone; q3wk Superior TTTF (primary endpoint)
Median TTTF: 5.6 vs 4.9 mo
(HR 0.77, 95% CI 0.625-0.91)

Chemotherapy

Endocrine therapy

Supportive therapy

  • Dexamethasone (Decadron) 7.5 to 8 mg (route not specified) once per day, started 1 day prior to docetaxel and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3)
  • G-CSF not recommended unless patients developed febrile neutropenia or severe infection
  • "Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"

14-day cycles


Regimen variant #2, 75 mg/m2 q3wk, 10 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Merseburger et al. 2022 (PRESIDE) 2014-2016 Phase 3 (C) Docetaxel, Enzalutamide, Prednisolone Seems to have inferior PFS

Chemotherapy

Endocrine therapy

21-day cycle for up to 10 cycles


Regimen variant #3, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY) 2004-2009 Phase 3 (C) Docetaxel & Prednisolone; q2wk Inferior TTTF
Fizazi et al. 2013 (ENTHUSE) 2008-NR Phase 3 (C) 1a. Docetaxel, Prednisolone, Zibotentan
1b. Docetaxel, Prednisone, Zibotentan 		Did not meet primary endpoint of OS

Chemotherapy

Endocrine therapy

  • Prednisolone (Millipred) 10 mg PO once per day on days 1 to 21
    • Alternative dosing in Fizazi et al. 2013: 5 mg PO twice per day

Supportive therapy

  • Dexamethasone (Decadron) 7.5 to 8 mg daily, started 1 day prior to docetaxel and stopped 1 to 2 days after docetaxel infusion (in other words, from day -1 to day 2 or 3); reference did not specify route of administration
  • G-CSF not recommended unless patients developed febrile neutropenia or severe infection
  • "Treatment with bisphosphonates, erythropoietin, and palliative radiation therapy was allowed"

21-day cycles

References

  1. PROSTY: Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, Luukkaa M, Nyandoto P, Hemminki A, Nilsson S, McCaffrey J, Asola R, Turpeenniemi-Hujanen T, Laestadius F, Tasmuth T, Sandberg K, Keane M, Lehtinen I, Luukkaala T, Joensuu H; PROSTY study group. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):117-24. Epub 2013 Jan 4. link to original article contains dosing details in manuscript PubMed NCT00255606
  2. ENTHUSE: Fizazi K, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, Nathan FE, McIntosh S, Pemberton K, Moul JW. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013 May 10;31(14):1740-7. Epub 2013 Apr 8. Erratum in: J Clin Oncol. 2014 Oct 20;32(30):3461. Fizazi, Karim S [Corrected to Fizazi, Karim]. link to original article contains dosing details in manuscript PubMed NCT00617669
  3. PRESIDE: Merseburger AS, Attard G, Åström L, Matveev VB, Bracarda S, Esen A, Feyerabend S, Senkus E, López-Brea Piqueras M, Boysen G, Gourgioti G, Martins K, Chowdhury S. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol. 2022 Nov;23(11):1398-1408. Epub 2022 Oct 18. link to original article contains dosing details in abstract PubMed NCT02288247

Mitoxantrone & Hydrocortisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kantoff et al. 1999 (CALGB 9182) 1992-1995 Phase 3 (E-RT-esc) Hydrocortisone Did not meet primary endpoint of OS

Chemotherapy

Endocrine therapy

21-day cycles

References

  1. CALGB 9182: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, Trump D, Winer EP, Vogelzang NJ. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol. 1999 Aug;17(8):2506-13. link to original article contains dosing details in manuscript PubMed

Mitoxantrone & Prednisone

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moore et al. 1994 NR Phase 2 (RT)
Tannock et al. 1996 (CCI-NOV22) 1990-1994 Phase 3 (E-RT-esc) Prednisone Superior palliation
Berry et al. 2002 1997-1999 Phase 3 (E-esc) Prednisone Seems to have superior TTTF
Petrylak et al. 2004 (SWOG S9916) 1999-2003 Phase 3 (C) Docetaxel & Estramustine Seems to have inferior OS
Tannock et al. 2004 (TAX 327) 2000-2002 Phase 3 (C) 1. Weekly Docetaxel & Prednisone Did not meet primary endpoint of OS
2. Every 3-week Docetaxel & Prednisone Inferior OS
de Bono et al. 2010 (TROPIC) 2007-01-02 to 2008-10-23 Phase 3 (C) Cabazitaxel & Prednisone Inferior OS

Prior treatment criteria

  • SWOG S9916: Hormone-independent prostate cancer
  • TAX 327: Disease progression during endocrine therapy, and no prior chemotherapy
  • TROPIC: Previous endocrine therapy, and failure of a docetaxel-containing regimen

Chemotherapy

Endocrine therapy

21-day cycle for up to 10 cycles

References

  1. Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J. Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol. 1994 Apr;12(4):689-94. link to original article PubMed
  2. CCI-NOV22: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64. link to original article PubMed
    1. HRQoL analysis: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol. 1999 Jun;17(6):1654-63. link to original article PubMed
  3. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002 Dec;168(6):2439-43. link to original article contains dosing details in abstract PubMed
  4. TAX 327: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1502-12. link to original article contains dosing details in manuscript PubMed
    1. Update: Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26(2):242-5. link to original article contains dosing details in manuscript PubMed
  5. SWOG S9916: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. link to original article PubMed NCT00004001
  6. TROPIC: de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54. link to original article contains dosing details in manuscript PubMed NCT00417079

Immunotherapy for metastatic castrate-resistant disease

Ipilimumab & RT

Ipilimumab & RT: Ipilimumab & Radiation Therapy

Regimen

Study Evidence Efficacy Patient population
Slovin et al. 2013 (CA184-017) Phase 1/2 ORR: 4% (95% CI n/a), PSA RR: 16%; Most had ADT, some had docetaxel use. 10 mg/kg cohort reported here.

Note: Lower doses of ipilimumab including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study.

Immunotherapy

Radiotherapy

  • Radiation therapy given focally at a single dose of 800 cGy per target bone lesion for up to three bone lesions per patient, given 24 to 48 h before the first ipilimumab dose

21-day cycle for 4 cycles

References

  1. CA184-017: Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013 Jul;24(7):1813-21. Epub 2013 Mar 27. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00323882

Sipuleucel-T monotherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Small et al. 2006 (D9901) 2000-01 to 2001-10 Phase 3 (E-RT-esc) Placebo Might have superior TTP (primary endpoint)
Higano et al. 2009 (D9902A) 2000-2003 Phase 3 (E-esc) Placebo Might have superior TTP (primary endpoint)
Kantoff et al. 2010 (IMPACTprostate) 2003-2007 Phase 3 (E-RT-esc) Placebo Seems to have superior OS (primary endpoint)
Median OS: 25.8 vs 21.7 mo
(HR 0.78, 95% CI 0.61-0.98)

Note: Higano et al. 2009 was a pooled update but also the first publication to describe results of D9902A. IMPACT should not be confused with the studies of the same name in breast cancer and colorectal cancer.

Immunotherapy

  • Sipuleucel-T (Provenge): leukapheresis followed 3 days later with at least 50 million autologous CD54+ cells activated with PAP-GM-CSF, to be done on weeks 0, 2, and 4

Supportive therapy

One course

References

  1. D9901: Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-94. link to original article PubMed NCT00005947
    1. Pooled update: Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. link to original article PubMed
  2. D9902A: Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. link to original article PubMed NCT01133704
  3. IMPACT: Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. link to original article contains dosing details in manuscript PubMed NCT00065442
  4. Safety analysis: Hall SJ, Klotz L, Pantuck AJ, George DJ, Whitmore JB, Frohlich MW, Sims RB. Integrated safety data from 4 randomized, double-blind, controlled trials of autologous cellular immunotherapy with sipuleucel-T in patients with prostate cancer. J Urol. 2011 Sep;186(3):877-81. Epub 2011 Jul 23. link to original article contains dosing details in manuscript PubMed

Radioactive agents for bony metastatic disease

Lutetium Lu 177 vipivotide tetraxetan monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sartor et al. 2021 (VISIONPrCA) 2018-06 to 2019-10 Phase 3 (E-RT-switch-ooc) Standard of care (excluding chemotherapy, immunotherapy, or Radium-223) Superior OS (co-primary endpoint)
Median OS: 15.3 vs 11.3 mo
(HR 0.62, 95% CI 0.52-0.74)

Radiotherapy

6-week cycles for 6 cycles

References

  1. TheraP: Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, McJannett MM, Stockler MR, Violet JA, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804. Epub 2021 Feb 11. link to original article PubMed NCT03392428
    1. Update: Hofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, Goh JC, Pattison DA, Tan TH, Kirkwood ID, Ng S, Francis RJ, Gedye C, Rutherford NK, Weickhardt A, Scott AM, Lee ST, Kwan EM, Azad AA, Ramdave S, Redfern AD, Macdonald W, Guminski A, Hsiao E, Chua W, Lin P, Zhang AY, Stockler MR, Williams SG, Martin AJ, Davis ID; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024 Jan;25(1):99-107. Epub 2023 Nov 30. link to original article PubMed
  2. VISIONPrCA: Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103. Epub 2021 Jun 23. link to original article link to PMC article PubMed NCT03511664
    1. HRQoL analysis: Fizazi K, Herrmann K, Krause BJ, Rahbar K, Chi KN, Morris MJ, Sartor O, Tagawa ST, Kendi AT, Vogelzang N, Calais J, Nagarajah J, Wei XX, Koshkin VS, Beauregard JM, Chang B, Ghouse R, DeSilvio M, Messmann RA, de Bono J. Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Jun;24(6):597-610. link to original article PubMed

Radium-223 monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Parker et al. 2013 (ALSYMPCA) 2008-2011 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 14 vs 11.2 mo
(HR 0.70, 95% CI 0.55-0.88) 		Superior EQ-5D score

Radiotherapy

28-day cycle for 6 cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nilsson et al. 2007 2004-2005 Randomized Phase 2 (E-esc) Placebo Might have superior OS (secondary endpoint)

Note: Patients in the study had "bone pain needing EBRT" (external beam radiation therapy). Treatment with radium 223 began within 7 days after EBRT.

Radiotherapy

28-day cycle for 4 cycles

References

  1. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8(7):587-94. link to original article contains dosing details in manuscript PubMed
    1. Update: Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, O'Bryan-Tear CG, Thuresson M, Bolstad B, Bruland ØS. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer. 2013 Mar;11(1):20-6. Epub 2012 Sep 26. link to original article contains dosing details in manuscript PubMed
  2. ALSYMPCA: Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. link to original article contains dosing details in manuscript PubMed NCT00699751
    1. Subgroup analysis: Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13. link to original article PubMed
    2. Subgroup analysis: Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17. link to original article PubMed
    3. HRQoL analysis: Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, Reuning-Scherer J, Shan M, Zhan L, Parker C. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74. Epub 2016 Feb 23. link to original article link to PMC article PubMed

Samarium-153 monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Resche et al. 1997 NR Phase 3 (E-esc) Samarium-153; 0.5 mCi/kg Seems to have superior pain control at week 4
Sartor et al. 2004 NR Phase 3 (E-esc) Samarium-152 (non-radioactive) Seems to have superior pain control at week 4

Radiotherapy

Supportive therapy

  • 1000 mL of fluid IV or PO given twice, 4 hours before and 6 hours after treatment

1 dose

References

  1. Resche I, Chatal JF, Pecking A, Ell P, Duchesne G, Rubens R, Fogelman I, Houston S, Fauser A, Fischer M, Wilkins D. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997 Sep;33(10):1583-91. link to original article contains dosing details in manuscript PubMed
  2. Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P; Quadramet 424Sm10/11 Study Group. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004 May;63(5):940-5. link to original article contains dosing details in manuscript PubMed

Measuring disease progression

  • Criteria used for disease progression in prostate cancer clinical trials, Prostate Cancer Clinical Trials Working Group 2 (PCWG2):[1]
    • Castrate level of serum testosterone is less than 50 ng/dL (less than 1.7 nmol/L)
      • However, there is controversy/disagreement in other references about whether a lower level should be used, such as less than 20 ng/dL (0.7 nmol/L)[2]
    • PSA rise
      • Starting PSA of at least 2 ng/mL
      • Rising PSA values which are measured at least 1-week apart
      • Pretherapy PSA doubling times (PSA-DT) can be estimated if there are at least 3 PSA values measured at least 4 weeks apart
    • Bony metastases
      • At least 2 new lesions indicates progressive disease
      • It is recommended to assess ambiguous results with other imaging modalities such as CT or MRI
    • Measurable lesions (RECIST) - this is a lower priority criteria by the PCWG2 because fewer patients have measurable lesions as compared to, for example, bony metastases
      • Baseline imaging involves chest imaging with x-ray or CT, CT or MRI of the abdomen/pelvis, and radionuclide bone scan
      • It is recommended that local disease is assessed by endorectal MRI or prostatic ultrasound
      • Neurologic symptoms should be assessed with MRI of the spine and base of the skull
      • Positron emission tomography (PET) is not recommended and is considered investigational
      • Measurable lesions should be followed with RECIST criteria
      • "Up to 10 visceral and nodal lesions in total should be recorded (with a maximum of five in any one organ)"
      • It is suggested that a lymph node must be at least 2 cm in maximal dimension on spiral CT to count as a target lesion.

Statistics

Links

Quality of life assessment tools

References

  1. ↑ Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. link to original article link to PMC article PubMed
  2. ↑ Oefelein MG, Feng A, Scolieri MJ, Ricchiutti D, Resnick MI. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology. 2000 Dec 20;56(6):1021-4. link to original article PubMed
  3. ↑ Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz MS, Leibel SA, Scardino PT, Slawin KM. Salvage Radiotherapy for Recurrent Prostate Cancer After Radical Prostatectomy. JAMA. 2004 Mar 17;291(11):1325-32. link to original article PubMed
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