Difference between revisions of "Prostate cancer"

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(added apalutamide)
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===References===
 
===References===
 
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1607529 link to original article] '''contains verified protocol'''  [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28146658 PubMed]
 
# 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. [http://www.nejm.org/doi/full/10.1056/NEJMoa1607529 link to original article] '''contains verified protocol'''  [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444881/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28146658 PubMed]
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=Hormonal therapy for non-metastatic castrate resistant disease=
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==Apalutamide monotherapy {{#subobject:a70eae |Regimen=1}}==
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{| class="wikitable" style="float:right; margin-left: 5px;"
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|-
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|[[#top|back to top]]
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|}
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===Regimen {{#subobject:#e085c7 |Variant=1}}===
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{| class="wikitable" style="width: 100%; text-align:center;"
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!Study
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![[Levels_of_Evidence#Evidence|Evidence]]
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![[Levels_of_Evidence|Metastasis-free survival]]
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!Comparator
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|Comparator [[Levels_of_Evidence|Metastasis-free survival]]
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![[Levels_of_Evidence#Efficacy|Efficacy]]
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|Pt Population
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|-
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|[https://www.nejm.org/doi/10.1056/NEJMoa1715546 Smith et al. 2017 (SPARTAN)]
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|style="background-color:#1a9851"|Phase III (E)
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|40.5 months
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|[[Prostate_cancer_-_historical#Placebo|Placebo]]
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|16.2 months
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|style="background-color:#1a9850"|Superior metastasis-free survival
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|Castrate-resistant, non-metastatic, PSA doubling time <10 months
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|-
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|}
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====Endocrine therapy====
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*[[Apalutamide (Erleada)]] 240 mg PO once per day
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**Patients should concurrently be receiving [[:Category:Endocrine therapy|GnRH analog]] or have had bilateral orchiectomy.
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'''Given until progression of disease or unacceptable toxicity'''
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===References===
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# '''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. [https://www.nejm.org/doi/10.1056/NEJMoa1715546 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1715546/suppl_file/nejmoa1715546_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29420164 PubMed]
  
 
=Hormonal therapy for metastatic or locally advanced disease=
 
=Hormonal therapy for metastatic or locally advanced disease=

Revision as of 16:10, 16 September 2018

Section editor
ChenEddy Sept2016.jpg
 Eddy J. Chen, MD
Boston, MA

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. If you still can't find it, please let us know so we can add it!


80 regimens on this page
111 variants on this page


Guidelines

ASCO

Older

ASCO & CCO

AUA

EAU/ESTRO/SIOG

ESMO

Older

NCCN

St Gallen

Induction ADT

ADT

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ADT: Androgen Deprivation Therapy

Regimen

Study Evidence Comparator Efficacy
Pisansky et al. 2014 (RTOG 9910) Phase III (C) ADT x 28 weeks Seems not superior

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

Hormonotherapy

8-week course

Subsequent treatment

References

  1. 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

Definitive therapy, including active surveillance

Active surveillance

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Regimen

Study Evidence Comparator Efficacy
Holmberg et al. 2002 (Scandinavian Prostatic Cancer Group Study Number 4) Phase III (E) Radical prostatectomy Seems to have inferior OS (*)
Fleshner et al. 2012 (REDEEM) Phase III (C) Dutasteride Inferior TTP

No antineoplastic therapy; consists of various strategies of close monitoring and re-biopsy. Efficacy for the Scandinavian Prostatic Cancer Group Study Number 4 is based on the 2005 update.

References

  1. Scandinavian Prostatic Cancer Group Study Number 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 Study Number 4. 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 Study No 4. 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. 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

ADT & RT

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ADT & RT: Androgen Deprivation Therapy & Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Bolla et al. 2009 (EORTC 22961) Non-randomized portion of RCT
Warde et al. 2011 (NCIC CTG PR.3/UK MRC PR07) Phase III (E) ADT alone Seems to have superior OS
Pisansky et al. 2014 (RTOG 9910) Non-randomized portion of RCT

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

Preceding treatment

  • RTOG 9910: ADT x 8 weeks versus ADT x 28 weeks

Hormonoradiotherapy

8-week course

Subsequent treatment

  • EORTC 22961: Continued ADT for 6 months versus 36 months

References

  1. 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 and 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
  2. 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 PR3/MRC UK PR07 investigators. 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
  3. 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
  4. 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

Flutamide, Goserelin, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Pilepich et al. 2001 (RTOG 86-10) Phase III (E) RT Seems to have superior cause-specific mortality
Hanks et al. 2003 (RTOG 92-02) Non-randomized portion of RCT
Denham et al. 2005 (TTROG 96.01) Phase III (E) Flutamide & Goserelin x 6 m, RT Not reported
RT Superior DFS
D'Amico et al. 2008 (DFCI 95-096) Phase III (E) RT Superior OS
Jones et al. 2011 (RTOG 94-08) Phase III (E) RT Seems to have superior OS

Hormonoradiotherapy

  • Flutamide (Eulexin) 250 mg PO three times per day, to start 2 months prior to radiation therapy and to continue at least through the end of radiation therapy
  • Goserelin (Zoladex) 3.6 mg SC once every 4 weeks, to start 2 months prior to radiation therapy and to continue at least through the end of radiation therapy
  • External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy

Subsequent treatment

References

  1. 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 verified protocol 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 verified protocol 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 protocol 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 verified protocol 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. PubMed
  3. TTROG 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 protocol PubMed
  4. 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
  5. 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 verified protocol PubMed

Flutamide, Leuprolide, RT

back to top

RT: Radiation Therapy

Variant #1, 4 months of ADT

Study Evidence Comparator Efficacy
Jones et al. 2011 (RTOG 94-08) Phase III (E) RT Seems to have superior OS

Hormonoradiotherapy

  • Flutamide (Eulexin) 250 mg PO three times per day x 4 months, to start 2 months prior to radiation therapy
  • Leuprolide (Lupron) 7.5 mg SC once every 4 weeks x 4 months, to start 2 months prior to radiation therapy
  • External beam radiotherapy is started 2 months after start of androgen deprivation therapy (ADT), 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional conedown to the prostate that resulted in a total dose of 65 to 70 Gy

Variant #2, indefinite ADT

Study Evidence Comparator Efficacy
Widmark et al. 2008 (SPCG-7/SFUO-3) Phase III (C) Flutamide & Leuprolide Superior OS

Hormonoradiotherapy

References

  1. 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 verified protocol PubMed
  2. 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 Study 7; Swedish Association for Urological Oncology 3. 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 verified protocol PubMed

Goserelin & RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Pilepich et al. 2005 (RTOG 85-31) Phase III (E) RT Superior DFS
Bolla et al. 1997 (EORTC 22863) Phase III (E) RT Superior OS

Hormonoradiotherapy

  • Goserelin (Zoladex) 3.6 mg SC once every 4 weeks, to start during the last week of radiation therapy and to continue indefinitely or until progression
  • External beam radiotherapy, 1.8 to 2 Gy per fraction, with an initial 44 to 46 Gy to the pelvis, then an additional boost to the prostate that resulted in a total dose of 65 to 70 Gy in definitive radiation patients; 60 to 65 Gy total dose for post-prostatectomy patients

References

  1. 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 protocol 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 protocol 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 verified protocol 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
    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

Adjuvant hormonal therapy

Bicalutamide & Goserelin

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Regimen

Study Evidence Comparator Efficacy
Dorff et al. 2011 (SWOG S9921) Phase III (C) ADT & Mitoxantrone Not reported

Dosing details are not available in the manuscript; this is the common dosing used.

Preceding treatment

  • Radical prostatectomy

Endocrine therapy

2-year course

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 protocol link to PMC article PubMed

Goserelin monotherapy

back to top

Regimen

Study Evidence Comparator Efficacy
Messing et al. 1999 (ECOG E3886) Phase III (E) No further treatment Seems to have superior OS
Hanks et al. 2003 (RTOG 92-02) Phase III (E) No further treatment Seems to have superior OS (*)

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. 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 verified protocol PubMed
    1. Update: Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. 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 protocol 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 verified protocol 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. PubMed

Observation

back to top

Regimen

Study Evidence Comparator Efficacy
Messing et al. 1999 (ECOG E3886) Phase III (C) Bilateral orchiectomy
Goserelin 		Seems to have inferior OS
Hanks et al. 2003 (RTOG 92-02) Phase III (C) Goserelin Seems to have inferior OS (*)

Efficacy of RTOG 92-02 based on the 2017 update. No further treatment after definitive therapy

Preceding treatment

References

  1. ECOG E3886: Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. 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 verified protocol PubMed
    1. Update: Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; Eastern Cooperative Oncology Group study EST 3886. 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 protocol 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 verified protocol 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. PubMed

Salvage ADT & radiotherapy

Bicalutamide & RT

back to top

RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Shipley et al. 2017 (RTOG 9601) Phase III (E) RT Seems to have superior OS

Preceding treatment

  • Prostatectomy with lymphadenectomy, with a postoperative detectable PSA level of 0.2 to 4.0 ng/mL

Endocrine & Radiotherapy

One course

References

  1. 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 verified protocol link to PMC article PubMed

Hormonal therapy for non-metastatic castrate resistant disease

Apalutamide monotherapy

back to top

Regimen

Study Evidence Metastasis-free survival Comparator Comparator Metastasis-free survival Efficacy Pt Population
Smith et al. 2017 (SPARTAN) Phase III (E) 40.5 months Placebo 16.2 months Superior metastasis-free survival Castrate-resistant, non-metastatic, PSA doubling time <10 months

Endocrine therapy

Given until progression of disease or unacceptable toxicity

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. link to original article link to supplementary appendix contains verified protocol PubMed

Hormonal therapy for metastatic or locally advanced disease

ADT & Abiraterone

back to top

ADT & Abiraterone: Androgen Deprivation Therapy & Abiraterone

Regimen

Study Evidence Comparator Efficacy
James et al. 2017 (STAMPEDE) Phase III (E) ADT Superior OS
Fizazi et al. 2017 (LATITUDE) Phase III (E) ADT Superior OS

Note: while LATITUDE allowed for a dose increase in prednisone, the FDA recommended dose is 5 mg PO once per day.

Endocrine therapy

Supportive medications

  • Prevention of mineralocorticoid excess with ONE of the following:
    • STAMPEDE except Switzerland: Prednisolone (Millipred) 5 mg PO once per day
    • LATITUDE and STAMPEDE 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 until progression unless radiotherapy planned, in which case continued for up to 2 years

References

  1. STAMPEDE: 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 verified protocol in supplement 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 verified protocol in supplement PubMed
    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

ADT & Docetaxel

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ADT & Docetaxel: Androgen Deprivation Therapy & Docetaxel

Variant #1, 6 cycles

Study Evidence Comparator Efficacy
Sweeney et al. 2015 (CHAARTED) Phase III (E) ADT alone Superior OS (*)
James et al. 2015 (STAMPEDE) Phase III (E) ADT alone Superior OS

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. In the 2018 update of CHAARTED, only patients with high-volume disease had a survival benefit.

Chemohormonal therapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #2, 9 cycles

Study Evidence Comparator Efficacy
Gravis et al. 2013 (GETUG-AFU 15) Phase III (E) ADT alone Seems not superior

Chemohormonal 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
    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 verified protocol Pubmed
    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. QoL analsysis: 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. STAMPEDE: 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 verified protocol PubMed

Bicalutamide monotherapy

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Regimen

Study Evidence Comparator Efficacy
Tyrrell et al. 1998 Phase III (E) Castration Not reported

Not approved for monotherapy in the United States. See combination regimens with Goserelin & Leuprolide.

Endocrine therapy

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. contains protocol 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 verified protocol PubMed

Bicalutamide & Goserelin

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Variant #1

Study Evidence Comparator Efficacy
Akaza et al. 2004 Phase III (E) Goserelin
Leuprolide 		Seems to have superior OS (*)

Note: efficacy is based on the 2009 update.

Endocrine therapy

Variant #2

Study Evidence Comparator Efficacy
Schellhammer et al. 1995 (Casodex Combination Study Group) Phase III (E) Bicalutamide & Leuprolide Not reported
Flutamide & Goserelin
Flutamide & Leuprolide 		Seems not superior (*)

Efficacy for the Casodex Combination Study Group is based on the 1997 final update.

Endocrine therapy

References

  1. Casodex Combination Study Group: Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. 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. 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; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol 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. contains protocol 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 verified protocol 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

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Variant #1

Study Evidence Comparator Efficacy
Akaza et al. 2004 Phase III (E) Goserelin
Leuprolide 		Seems to have superior OS (*)

Note: efficacy is based on the 2009 update.

Endocrine therapy

Variant #2

Study Evidence Comparator Efficacy
Schellhammer et al. 1995 (Casodex Combination Study Group) Phase III (E) Bicalutamide & Goserelin Not reported
Flutamide & Goserelin
Flutamide & Leuprolide 		Seems not superior (*)

Efficacy for the Casodex Combination Study Group is based on the 1997 final update.

Endocrine therapy

References

  1. Casodex Combination Study Group: Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. 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. 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; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol 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. contains protocol 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 verified protocol 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

Degarelix monotherapy

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Example orders

Variant #1, 240/80

FDA-recommended dose
Study Evidence Comparator Efficacy
Klotz et al. 2008 (CS21) Phase III (E) Degarelix 240/160 Non-inferior testosterone suppression
Leuprolide Non-inferior testosterone suppression

Endocrine therapy

  • Degarelix (Firmagon) 240 mg (given as 2 x 120 mg injections) SC once, then 80 mg SC once every 28 days

Continued indefinitely

Variant #2, 240/160

Study Evidence Comparator Efficacy
Klotz et al. 2008 (CS21) Phase III (E) Degarelix 240/80 Non-inferior testosterone suppression
Leuprolide Non-inferior testosterone suppression

Endocrine therapy

  • Degarelix (Firmagon) 240 mg (given as 2 x 120 mg injections) SC once, then 160 mg SC once every 28 days

Continued indefinitely

Variant #3, 240/480

Study Evidence Comparator Efficacy
Ozono et al. 2018 (3550-CL-0010) Phase III (E) Goserelin Non-inferior testosterone suppression

Endocrine therapy

Continued indefinitely

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 verified protocol PubMed
    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 verified protocol 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

Flutamide monotherapy

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Regimen

Study Evidence Comparator Efficacy
Boccon-Gibod et al. 1997 Phase III (E) Orchiectomy Seems not superior
Fosså et al. 2001 (EORTC 30903) Phase III (E) Prednisone Seems not superior

Not approved for monotherapy in the United States. See combination regimens with Goserelin & Leuprolide.

Endocrine therapy

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. contains protocol 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 protocol PubMed

Flutamide & Goserelin

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Regimen

Study Evidence Comparator Efficacy
Denis et al. 1993 (EORTC 30853) Phase III (E) Bilateral orchiectomy Seems to have superior OS
Schellhammer et al. 1995 (Casodex Combination Study Group) Phase III (C) Bicalutamide & Goserelin
Bicalutamide & Leuprolide 		Seems not superior (*)
Flutamide & Leuprolide Not reported
Hussain et al. 2013 (SWOG-9346) Phase III (C) Intermittent ADT Inconclusive whether non-inferior

Efficacy for the Casodex Combination Study Group is based on the 1997 final update.

Endocrine therapy

References

  1. EORTC 30853: Denis LJ, Carnelro de Moura JL, Bono A, Sylvester R, Whelan P, Newling D, Depauw M; EORTC GU Group and EORTC Data Center. 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 protocol PubMed
    1. 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. PubMed
  2. Casodex Combination Study Group: 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 protocol 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. contains protocol 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 verified protocol in supplementary protocol PubMed

Flutamide & Leuprolide

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Variant #1, daily Lupron

Study Evidence Comparator Efficacy
Crawford et al. 1989 (SWOG-8494) Phase III (E) Leuprolide Seems to have superior OS

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

Endocrine therapy

Continued indefinitely

Variant #2, 1-month depot Lupron

Study Evidence Comparator Efficacy
Schellhammer et al. 1995 (Casodex Combination Study Group) Phase III (C) Bicalutamide & Goserelin
Bicalutamide & Leuprolide 		Seems not superior (*)
Flutamide & Goserelin Not reported
Hussain et al. 2013 (SWOG-9346) Phase III (C) Intermittent ADT Inconclusive whether non-inferior

Efficacy for the Casodex Combination Study Group is based on the 1997 final update.

Endocrine therapy

Continued indefinitely

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 verified protocol PubMed
  2. Casodex Combination Study Group: Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer; Casodex Combination Study Group. 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. 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; CASODEX Combination Study Group. Cancer. 1996 Nov 15;78(10):2164-9. link to original article contains protocol 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. contains protocol 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 verified protocol in supplementary protocol PubMed

Goserelin monotherapy

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Example orders

Variant #1, 28-day cycles

Study Evidence Comparator Efficacy
Soloway et al. 1991 (Zoladex Prostate Study Group) Phase III (E) Bilateral orchiectomy Seems not superior
Kaisary et al. 1991 Phase III (E) Bilateral orchiectomy Seems not superior

Endocrine therapy

Continued indefinitely

Variant #2, 84-day cycles

Study Evidence Comparator Efficacy
Ozono et al. 2018 (3550-CL-0010) Phase III (C) Degarelix Non-inferior testosterone suppression

Endocrine therapy

Continued indefinitely

References

  1. Zoladex Prostate Study Group: 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 verified protocol 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. PubMed
  3. 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

Intermittent ADT

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Regimen

To be completed

References

  1. 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

Leuprolide monotherapy

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Example orders

Variant #1, daily

Study Evidence Comparator Efficacy
Crawford et al. 1989 (SWOG-8494) Phase III (C) Flutamide & Leuprolide Seems to have inferior OS

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

Endocrine therapy

Continued indefinitely

Variant #2, 1-month depot, 3.75 mg

Study Evidence Comparator Efficacy
Akaza et al. 2004 Phase III (C) Bicalutamide & Goserelin
Bicalutamide & Leuprolide 		Seems to have inferior OS (*)

Note: efficacy is based on the 2009 update.

Endocrine therapy

Variant #3, 1-month depot, 7.5 mg

Study Evidence Comparator Efficacy
Klotz et al. 2008 (CS21) Phase III (C) Degarelix 240/80 Non-inferior testosterone suppression
Degarelix 240/160 Non-inferior testosterone suppression

Endocrine therapy

Variant #4, 3-month depot

Study Evidence
Sharifi et al. 1996 Phase II

Endocrine therapy

Variant #5, 4-month depot

Study Evidence
Sharifi et al. 1998 Phase II

Endocrine therapy

Other

Supportive medications

  • (varies depending on reference):
  • Bicalutamide (Casodex) 50 mg PO once per day for protection from testosterone flare

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 verified protocol PubMed
  2. 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 verified protocol PubMed
  3. 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
  4. 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 verified protocol 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
  5. 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 verified protocol PubMed
    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 verified protocol PubMed

Nilutamide & Orchiectomy

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Regimen

Study Evidence Comparator Efficacy
Janknegt et al. 1993 (International Anandron Study Group) Phase III (E) Orchiectomy Superior PFS

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

Endocrine therapy

References

  1. International Anandron Study Group: 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 SD 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. 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. 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 verified protocol PubMed

Metastatic disease, second-line hormonal therapy

Abiraterone & Prednisone

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Regimen

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
de Bono et al. 2011 (COU-AA-301) Phase III (E) 14% (95% CI n/a), 29% Prednisone 3% (95% CI n/a), 6% Superior OS Chemo-exposed
Ryan et al. 2013 (COU-AA-302) Phase III (E) 36% (95% CI n/a), 62% Prednisone 16% (95% CI n/a), 24% Seems to have superior OS Chemo-naive
Attard et al. 2018 (PLATO) Phase III (C) Abiraterone, Enzalutamide, Prednisone Seems not superior Chemo-naive

Preceding treatment

Endocrine therapy

Continued indefinitely

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 verified protocol link to PMC article PubMed
    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 verified protocol 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 verified protocol 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 verified protocol link to PMC article PubMed
    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. 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 verified protocol PubMed

Antiandrogen withdrawal

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Regimen

Study Evidence Comparator Efficacy
Small et al. 2004 (CALGB 9583) Phase III (C) Ketoconazole & Hydrocortisone Inferior PSA response

Refers to cessation of antiandrogen therapy.

References

  1. 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 verified protocol PubMed

Bicalutamide monotherapy

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Regimen

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
Penson et al. 2016 (STRIVE) Randomized Phase II (C) pts w/ measurable disease: 14% (95% CI n/a), 31% (95% CI n/a) Enzalutamide pts w/ measurable disease: 60% (95% CI n/a), 81% (95% CI n/a) Inferior PFS Chemo-naive, abi and keto-naive

Patients continued ADT while on study; details not provided.

Endocrine therapy

Continued until progression

References

  1. 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 protocol PubMed

Enzalutamide monotherapy

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Variant #1, 160 mg/d

Study Evidence Efficacy, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
Scher et al. 2012 (AFFIRM) Phase III (E) 29% (95% CI n/a), 54% Placebo 4% (95% CI n/a), 2% Superior OS Chemo-exposed (docetaxel)
Beer et al. 2014 (PREVAIL) Phase III (E) 59% (95% CI n/a), 78% Placebo 5% (95% CI n/a), 3% Superior OS Chemo and abiraterone naive
Penson et al. 2016 (STRIVE) Randomized Phase II (E) 60% (95% CI n/a), 81% Bicalutamide 14% (95% CI n/a), 31% Superior PFS Chemo and bicalutamide naive
Attard et al. 2018 (PLATO) Non-randomized portion of RCT Chemo-naive

Patients in STRIVE & PLATO continued ADT while on study or had a history of bilateral orchiectomy; details not provided.

Endocrine therapy

Continued indefinitely

Subsequent treatment

Variant #2, 240 mg/d

Study Evidence
Scher et al. 2010 (S-3100-1-01) Phase I/II

Note: this is the reported MTD from the phase I portion of the trial; however, it is NOT the dose used in subsequent phase III 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 protocol PubMed
  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 verified protocol PubMed
  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
    1. 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
    2. HRQoL analysis: Devlin N, Herdman M, Pavesi M, Phung, 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. 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 protocol PubMed
  5. 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 verified protocol PubMed

Ketoconazole & Hydrocortisone

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Regimen

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
Small et al. 2004 (CALGB 9583) Phase III (E) pts w/ measurable disease: 20% (95% CI 11 - 32), 27% (95% CI 20 - 35) Antiandrogen withdrawal pts w/ measurable disease: 2% (95% CI 0 - 11), 11% (95% CI 7 - 17) Superior PSA response Progression at ADT, i.e. CRPC

Endocrine therapy

References

  1. 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 verified protocol PubMed

Ketoconazole, Hydrocortisone, Dutasteride

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Regimen

Study Evidence
Taplin et al. 2009 Phase II

Endocrine therapy

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 verified protocol link to PMC article PubMed

Prednisone monotherapy

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Variant #1, 5 mg BID

Study Evidence Comparator Efficacy
Tannock et al. 1996 Phase III (C) Mitoxantrone & Prednisone Inferior palliation
de Bono et al. 2011 (COU-AA-301) Phase III (C) Abiraterone & Prednisone Inferior OS
Ryan et al. 2013 (COU-AA-302) Phase III (C) Abiraterone & Prednisone Seems to have inferior OS
Smith et al. 2016 (COMET-1) Phase III (C) Cabozantinib Seems not superior

Hormonotherapy

Continued indefinitely

Variant #2, 5 mg QID

Study Evidence Comparator Efficacy
Fosså et al. 2001 (EORTC 30903) Phase III (C) Flutamide Seems not superior

Hormonotherapy

Continued indefinitely

References

  1. 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 verified protocol 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
  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 protocol PubMed
  3. 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 verified protocol link to PMC article PubMed
    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 verified protocol 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 verified protocol PubMed
  4. 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 verified protocol link to PMC article PubMed
    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 SD article PubMed
  5. 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 verified protocol PubMed

Chemotherapy for metastatic castrate-resistant disease

Cabazitaxel & Prednisone

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Example orders

Variant #1, 20 mg/m2

Study Evidence Comparator Efficacy
Oudard et al. 2017 (FIRSTANA) Phase III (E) Cabazitaxel 25 mg/m2 & Prednisone Seems not superior
Docetaxel & Prednisone Seems not superior
Eisenberger et al. 2017 (PROSELICA) Phase III (E) Cabazitaxel 25 mg/m2 & Prednisone Non-inferior OS

Chemotherapy

21-day cycles

Variant #2, 25 mg/m2

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
de Bono et al. 2010 (TROPIC) Phase III (E) 14% (95% CI 10-19)
39% (95% CI 34-44) (*) 		Mitoxantrone & Prednisone 4% (95% CI 2-7)
18% (95% CI 14-22) (*) 		Superior OS Progressed on docetaxel
Oudard et al. 2017 (FIRSTANA) Phase III (E) Cabazitaxel 20 mg/m2 & Prednisone Seems not superior
Docetaxel & Prednisone Seems not superior
Eisenberger et al. 2017 (PROSELICA) Phase III (C) Cabazitaxel 20 mg/m2 & Prednisone Non-inferior OS
Beer et al. 2017 (AFFINITY) Phase III (C) Cabazitaxel, Prednisone, Custirsen Seems not superior Progressed on docetaxel

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

Chemotherapy

Supportive medications

21-day cycle for up to 10 cycles (TROPIC) or until progression (PROSELICA)

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed
  3. 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 verified protocol in supplement PubMed
  4. 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

Cabozantinib monotherapy

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Variant #1, 60 mg/d

Study Evidence Comparator Efficacy
Smith et al. 2016 (COMET-1) Phase III (E) Prednisone Seems not superior

Chemotherapy

Variant #2, 100 mg/d

Study Evidence
Smith et al. 2012 Phase II

Chemotherapy

References

  1. 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 verified protocol link to PMC article PubMed
  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 verified protocol PubMed

Carboplatin & Docetaxel

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Example orders

Variant #1

Study Evidence
Ross et al. 2008 Phase II

Patients enrolled in the trial had hormone-refractory prostate cancer and progression of disease during docetaxel treatment or within 45 days of stopping docetaxel treatment.

Chemotherapy

Supportive medications

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

21-day cycles

Variant #2, weekly docetaxel

Study Evidence
Reuter et al. 2010 Phase II

Patients enrolled in the trial had progression of disease on docetaxel chemotherapy 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.
  • Prednisone (Sterapred) 5 mg PO BID on days 1 to 28

Supportive medications

  • "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. 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 verified protocol PubMed
  2. 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
  3. 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 verified protocol PubMed

Carboplatin & Paclitaxel

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Variant #1

Study Evidence
Kentepozidis et al. 2012 Phase II

Chemotherapy

Supportive medications

28-day cycles

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 verified protocol PubMed
  2. Kentepozidis N, Soultati A, Giassas S, Vardakis N, Kalykaki A, Kotsakis A, Papadimitraki E, Pantazopoulos N, Bozionellou V, Georgoulias V. 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 verified protocol PubMed

Cyclophosphamide, Prednisone, Diethylstilbestrol

CPD: Cyclophosphamide, Prednisone, Diethylstilbestrol

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Regimen

Study Evidence Efficacy
Hellerstedt et al. 2003 Phase II 50% or greater decline in PSA: 42%

Chemotherapy

Supportive medications

30-day cycles

References

  1. Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, Olson K, Smith DC. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003 Oct 15;98(8):1603-10. link to original article contains verified protocol PubMed

Docetaxel & Prednisone

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Example orders

Variant #1, 30 mg/m2 weekly

Study Evidence Comparator Efficacy
Tannock et al. 2004 (TAX 327) Phase III (E) Every 3-week Docetaxel & Prednisone Not reported
Mitoxantrone & Prednisone Seems not superior

Chemotherapy

Supportive medications

42-day cycle for up to 5 cycles

Variant #2, 50 mg/m2 bi-weekly

Study Evidence Comparator Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY Phase III (E) Every 3-weeks Docetaxel & Prednisone Seems to have superior TTTF

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 7.5 to 8 mg once per day, started 1 day before Docetaxel (Taxotere) 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"

28-day cycles

Variant #3, 75 mg/m2 q3wk, limited duration

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
Tannock et al. 2004 (TAX 327) Phase III (E) pts w/ measurable disease:12% (95% CI, 7-19), 45% (95% CI, 40-51) Weekly Docetaxel & Prednisone pts w/ measurable disease:8% (95% CI, 4-14), 48% (95% CI, 42-54) Not reported Chemo-naive
Mitoxantrone & Prednisone pts w/ measurable disease:7% (95% CI, 3-12), 32% (95% CI, 26-37) Superior OS Chemo-naive
Scher et al. 2011 (ASCENT) Phase III (C) Calcitriol, Docetaxel, Prednisone Superior OS
Quinn et al. 2013 (SWOG S0421) Phase III (C) Atrasentan, Docetaxel, Prednisone Seems not superior

Chemotherapy

Supportive medications

21-day cycle for up to 10 cycles (TAX 327; ASCENT) or 12 cycles (SWOG S0421)

Variant #4, 75 mg/m2 q3wk, indefinite, with prednisone

Study Evidence Comparator Efficacy
Kelly et al. 2012 (CALGB 90401) Phase III (C) Docetaxel, Prednisone, Bevacizumab Seems not superior
Fizazi et al. 2013 (ENTHUSE) Phase III (C) Docetaxel, Prednisone, Zibotentan Seems not superior
Tannock et al. 2013 (VENICE) Phase III (C) Dasatinib, Docetaxel, Prednisone Seems not superior
Araujo et al. 2013 (READY) Phase III (C) Dasatinib, Docetaxel, Prednisone Seems not superior
Petrylak et al. 2015 (MAINSAIL) Phase III (C) Docetaxel, Lenalidomide, Prednisone Superior OS
Chi et al. 2017 (SYNERGY) Phase III (C) Custirsen, Docetaxel, Prednisone Seems not superior
Oudard et al. 2017 (FIRSTANA) Phase III (C) Cabazitaxel 20 mg/m2 & Prednisone Seems not superior
Cabazitaxel 25 mg/m2 & Prednisone Seems not superior

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

Chemotherapy

21-day cycles

Variant #5, 75 mg/m2 q3wk, indefinite, with prednisolone

Study Evidence Comparator Efficacy
Kellokumpu-Lehtinen et al. 2013 (PROSTY) Phase III (C) Every 2-weeks Docetaxel & Prednisone Seems to have inferior TTTF
Fizazi et al. 2013 (ENTHUSE) Phase III (C) Docetaxel, Prednisolone, Zibotentan Seems not superior

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 7.5 to 8 mg daily, started 1 day before Docetaxel (Taxotere) 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. 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 verified protocol 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 verified protocol PubMed
  2. ASCENT: 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 verified protocol link to PMC article PubMed
  4. 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; for the 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 verified protocol PubMed
  5. 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 verified protocol PubMed
  6. 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 protocol PubMed
  7. 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 verified protocol PubMed
  8. 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 protocol link to PMC article PubMed
  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 protocol PubMed
  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 protocol PubMed
  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 verified protocol PubMed

Mitoxantrone & Prednisone

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Example orders

Regimen

Study Evidence ORR, PSA RR Comparator Comparator ORR, PSA RR Efficacy Pt Population
Tannock et al. 1996 Phase III (E) Prednisone Superior palliation
Tannock et al. 2004 (TAX 327) Phase III (C) pts w/ measurable disease: 7% (95% CI 3-12), 32% (95% CI 26-37) Weekly Docetaxel & Prednisone pts w/ measurable disease: 8% (95% CI 4-14), 48% (95% CI 42-54) Seems not superior Chemo naive
Every 3-week Docetaxel & Prednisone pts w/ measurable disease: 12% (95% CI 7-19), 45% (95% CI 40-51) Inferior OS Chemo naive
Petrylak et al. 2004 (SWOG S9916) Phase III (C) Docetaxel & Estramustine Seems to have inferior OS
de Bono et al. 2010 (TROPIC) Phase III (C) pts w/ measurable disease:
4.4% (95% CI 1.6 - 7.2), 17.8% (95% CI 13.7 - 22.0) 		Cabazitaxel & Prednisone pts w/ measurable disease:
14.4% (95% CI 9.6 - 19.3), 39.2% (95% CI 33.9 - 44.5) 		Inferior OS Progressed on docetaxel

Chemotherapy

21-day cycle for up to 10 cycles

References

  1. 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
  2. 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 verified protocol 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 verified protocol PubMed
  3. 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
  4. 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 verified protocol PubMed

Olaparib monotherapy

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Regimen

Study Evidence
Kaufman et al. 2014 Phase II, <20 pts in subgroup
Mateo et al. 2015 (TOPARP-A) Phase II
  • Patients in Kaufman et al. 2014 had germline BRCA1/2 mutations and had progression on hormonal and one systemic therapy.
  • Patients in Mateo et al. 2015 (TOPARP-A) who were found to have homozygous deletions, deleterious mutations, or both in DNA-repair genes were much more likely to respond to olaparib.

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. link to original article contains verified protocol PubMed
  2. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. link to original article contains verified protocol link to PMC article PubMed

Immunotherapy for metastatic castrate-resistant disease

Ipilimumab & RT

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RT: Radiation Therapy

Regimen

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

Immunoradiotherapy

  • Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes once on day 1
    • Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study
  • Radiation therapy given focally at a single dose of 8 Gy 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. 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. link to original article contains verified protocol link to PMC article PubMed

Sipuleucel-T monotherapy

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Example orders

Regimen

Study Evidence Comparator Efficacy
Kantoff et al. 2010 (IMPACT) Phase III (E) Placebo Seems to have superior OS

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 medications

References

  1. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Radioactive agents for bony metastatic disease

Radium-223 monotherapy

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Variant #1

Study Evidence Comparator Efficacy Toxicity
Parker et al. 2013 (ALSYMPCA) Phase III (E) Placebo Superior OS Superior EQ-5D score

Radiotherapy

28-day cycle for 6 cycles

Variant #2

Study Evidence Comparator Efficacy
Nilsson et al. 2007 Randomized Phase II (E) Placebo Might have superior OS

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 verified protocol 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 verified protocol 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 verified protocol PubMed
    1. Subgroup analysis: Prof Peter Hoskin MD, Prof Oliver Sartor MD, Prof Joe M O'Sullivan MD, Dag Clement Johannessen MD, Svein I Helle MD, John Logue FRCR, David Bottomley FRCR, Prof Sten Nilsson MD, Prof Nicholas J Vogelzang MD, Fang Fang PhD, Mona Wahba MD, Anne-Kirsti Aksnes PhD, Christopher Parker MD. 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. The Lancet Oncology, Volume 15, Issue 12, Pages 1397 - 1406, November 2014. link to original article
    2. 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

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Regimen

Study Evidence Comparator Efficacy
Resche et al. 1997 Phase III (E) Samarium-153 0.5 mCi/kg Seems to have superior pain control at week 4
Sartor et al. 2004 (Quadramet 424Sm10/11 Study Group) Phase III (E) Samarium-152 (non-radioactive) Seems to have superior pain control at week 4

Radiotherapy

Supportive medications

  • 1000 mL of fluid PO/IV 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 verified protocol 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 verified protocol 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 2.0 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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