Prostate cancer - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main prostate cancer page for current regimens.


Neoadjuvant therapy

No neoadjuvant therapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eastham et al. 2020 (CALGB 90203) 2006-2015 Phase III (C) ADT & Docetaxel Did not meet primary endpoint of BPFS

No treatment prior to surgical resection.

Subsequent treatment

References

  1. CALGB 90203: Eastham JA, Heller G, Halabi S, Monk JP 3rd, Beltran H, Gleave M, Evans CP, Clinton SK, Szmulewitz RZ, Coleman J, Hillman DW, Watt CR, George S, Sanda MG, Hahn OM, Taplin ME, Parsons JK, Mohler JL, Small EJ, Morris MJ. Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer. J Clin Oncol. 2020 Sep 10;38(26):3042-3050. Epub 2020 Jul 24. link to original article link to PMC article PubMed NCT00430183

Adjuvant therapy

Observation

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Messing et al. 1999 (ECOG E3886) 1988-1993 Phase III (C) 1. Bilateral orchiectomy
2. Goserelin
Seems to have inferior OS
Hanks et al. 2003 (RTOG 92-02) 1992-1995 Phase III (C) Goserelin Seems to have inferior OS1
Schweizer et al. 2013 (TAX-3501) 2005-2007 Phase III (C) 1. Docetaxel & Leuprolide
2. Leuprolide
Not reported
Ahlgren et al. 2018 (SPCG 12) 2005-2010 Phase III (C) Docetaxel Might have superior OS
Kellokumpu-Lehtinen et al. 2019 (SPCG-13) NR in abstract Phase III (C) Docetaxel Did not meet primary endpoint of BDFS
Lin et al. 2020 (VA 553) 2006-NR in abstract Phase III (C) Docetaxel & Prednisone Did not meet primary endpoint of PFS

1Reported efficacy of RTOG 92-02 is based on the 2017 update.
Note: TAX-3501 was closed early due to poor accrual, and statistical comparisons were not made. No further treatment after definitive therapy

Preceding treatment

References

  1. ECOG E3886: Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D; ECOG. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999 Dec 9;341(24):1781-8. link to original article contains verified protocol PubMed
    1. Update: Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, di'SantAgnese PA, Trump D; ECOG. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9. link to original article PubMed
  2. RTOG 92-02: Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, Horwitz EM, Lawton C, Rosenthal SA, Sandler HM, Shipley WU; Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol. 2003 Nov 1;21(21):3972-8. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. link to original article contains 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. link to original article link to PMC article PubMed
  3. TAX-3501: Schweizer MT, Huang P, Kattan MW, Kibel AS, de Wit R, Sternberg CN, Epstein JI, Eisenberger MA. Adjuvant leuprolide with or without docetaxel in patients with high-risk prostate cancer after radical prostatectomy (TAX-3501): important lessons for future trials. Cancer. 2013 Oct 15;119(20):3610-8. Epub 2013 Aug 13. link to original article link to PMC article PubMed NCT00283062
  4. SPCG 12: Ahlgren GM, Flodgren P, Tammela TLJ, Kellokumpu-Lehtinen P, Borre M, Angelsen A, Iversen JR, Sverrisdottir A, Jonsson E, Sengelov L; Scandinavian Prostate Cancer Group. Docetaxel versus surveillance after radical prostatectomy for high-risk prostate cancer: results from the prospective randomised, open-label phase 3 Scandinavian Prostate Cancer Group 12 trial. Eur Urol. 2018 Jun;73(6):870-876. Epub 2018 Feb 1. link to original article PubMed NCT00376792
  5. SPCG-13: Kellokumpu-Lehtinen PL, Hjälm-Eriksson M, Thellenberg-Karlsson C, Åström L, Franzen L, Fransson AS, Leskinen MJ, Zeke M, Huttunen T, Ginman C; Scandinavian Prostate Cancer Group. Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer-Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial. Eur Urol. 2019 Dec;76(6):823-830. Epub 2019 Aug 20. Erratum in: Eur Urol. 2020 Dec;78(6):e241-e242. link to original article PubMed NCT00653848
  6. VA 553: Lin DW, Shih MC, Aronson W, Basler J, Beer TM, Brophy M, Cooperberg M, Garzotto M, Kelly WK, Lee K, McGuire V, Wang Y, Lu Y, Markle V, Nseyo U, Ringer R, Savage SJ, Sinnott P, Uchio E, Yang CC, Montgomery RB. Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study. Eur Urol. 2020 May;77(5):563-572. Epub 2020 Jan 8. link to original article PubMed NCT00132301

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bosland et al. 2013 (UIC-2006-0706) 1997-2010 Phase III (C) Soy protein isolate Did not meet primary endpoint of biochemical recurrence rate

No further treatment after definitive therapy

Preceding treatment

References

  1. UIC-2006-0706: Bosland MC, Kato I, Zeleniuch-Jacquotte A, Schmoll J, Enk Rueter E, Melamed J, Kong MX, Macias V, Kajdacsy-Balla A, Lumey LH, Xie H, Gao W, Walden P, Lepor H, Taneja SS, Randolph C, Schlicht MJ, Meserve-Watanabe H, Deaton RJ, Davies JA. Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial. JAMA. 2013 Jul 10;310(2):170-8. link to original article link to PMC article PubMed NCT00765479

Therapy for non-metastatic castrate resistant disease

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Nelson et al. 2008 (M00-244) 2001-2003 Phase III (C) Atrasentan Did not meet primary endpoint of TTP
Miller et al. 2013 (ENTHUSE M0) 2008-2011 Phase III (C) Zibotentan Did not meet primary endpoint of OS

No active antineoplastic therapy.

References

  1. M00-244: Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, Qian J, Steinberg J, Carducci M; Atrasentan Phase 3 Study Group. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008 Nov 1;113(9):2478-87. link to original article link to PMC article PubMed NCT00036556
  2. ENTHUSE M0: Miller K, Moul JW, Gleave M, Fizazi K, Nelson JB, Morris T, Nathan FE, McIntosh S, Pemberton K, Higano CS. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2013 Jun;16(2):187-92. Epub 2013 Feb 5. link to original article PubMed NCT00626548

Therapy for metastatic castrate-resistant disease

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Carducci et al. 2007 2001-2002 Phase III (C) Atrasentan Did not meet primary endpoint of TTP
Kantoff et al. 2010 (IMPACTprostate) 2003-2007 Phase III (C) Sipuleucel-T Seems to have inferior OS
Nilsson et al. 2007 2004-2005 Randomized Phase II (C) Radium-223 Might have inferior OS
Nelson et al. 2012 (ENTHUSE M1) 2007-2009 Phase III (C) Zibotentan Did not meet primary endpoint of OS
Parker et al. 2013 (ALSYMPCA) 2008-2011 Phase III (C) Radium-223 Inferior OS Inferior EQ-5D score
Scher et al. 2012 (AFFIRM) 2009-2010 Phase III (C) Enzalutamide Inferior OS
Kwon et al. 2014 (CA184-043) 2009-2012 Phase III (C) Ipilimumab Might have inferior OS
Beer et al. 2014 (PREVAIL) 2010-2012 Phase III (C) Enzalutamide Inferior OS Worse HRQoL
Beer et al. 2016 (CA184-095) 2010-NR Phase III (C) Ipilimumab Seems not superior
Sternberg et al. 2016 (10TASQ10) 2011-2012 Phase III (C) Tasquinimod Inferior rPFS
Gulley et al. 2019 (PROSPECT) 2011-2015 Phase III (C) 1. PROSTVAC
2. PROSTVAC & GM-CSF
Did not meet primary endpoint of OS

No active antineoplastic therapy.

References

  1. D9901: Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-94. link to original article PubMed
    1. Pooled Update: Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-9. link to original article PubMed
  2. 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
  3. Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ, Isaacson JD, Nelson JB; Atrasentan Phase III Study Group Institutions. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007 Nov 1;110(9):1959-66. link to original article PubMed
  4. IMPACT: Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. link to original article contains verified protocol PubMed
  5. ENTHUSE M1: Nelson JB, Fizazi K, Miller K, Higano C, Moul JW, Akaza H, Morris T, McIntosh S, Pemberton K, Gleave M. Phase 3, randomized, placebo-controlled study of zibotentan (ZD4054) in patients with castration-resistant prostate cancer metastatic to bone. Cancer. 2012 Nov 15;118(22):5709-18. Epub 2012 Jul 11. link to original article PubMed NCT00554229
  6. 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 NCT00974311
  7. 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 NCT00699751
    1. Subgroup analysis: Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Bruland ØS, Parker C. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13. link to original article PubMed
    2. Subgroup analysis: Hoskin P, Sartor O, O'Sullivan JM, Johannessen DC, Helle SI, Logue J, Bottomley D, Nilsson S, Vogelzang NJ, Fang F, Wahba M, Aksnes AK, Parker C. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17. link to original article PubMed
    3. HRQoL analysis: Nilsson S, Cislo P, Sartor O, Vogelzang NJ, Coleman RE, O'Sullivan JM, Reuning-Scherer J, Shan M, Zhan L, Parker C. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016 May;27(5):868-74. Epub 2016 Feb 23. link to original article link to PMC article PubMed
  8. CA184-043: Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR; CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):700-12. Epub 2014 May 13. link to original article link to PMC article PubMed NCT00861614
    1. Update: Fizazi K, Drake CG, Beer TM, Kwon ED, Scher HI, Gerritsen WR, Bossi A, den Eertwegh AJMV, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Danielli R, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, McHenry MB, Chen A, Logothetis C; CA184-043, Investigators. Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors. Eur Urol. 2020 Dec;78(6):822-830. Epub 2020 Aug 15. link to original article PubMed
  9. PREVAIL: Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1. link to original article link to PMC article PubMed NCT01212991
    1. 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
  10. 10TASQ10: Sternberg C, Armstrong A, Pili R, Ng S, Huddart R, Agarwal N, Khvorostenko D, Lyulko O, Brize A, Vogelzang N, Delva R, Harza M, Thanos A, James N, Werbrouck P, Bögemann M, Hutson T, Milecki P, Chowdhury S, Gallardo E, Schwartsmann G, Pouget JC, Baton F, Nederman T, Tuvesson H, Carducci M. Randomized, double-blind, placebo-controlled phase III study of tasquinimod in men with metastatic castration-resistant prostate cancer. J Clin Oncol. 2016 Aug 1;34(22):2636-43. Epub 2016 Jun 13. link to original article PubMed NCT01234311
  11. CA184-095: Beer TM, Kwon ED, Drake CG, Fizazi K, Logothetis C, Gravis G, Ganju V, Polikoff J, Saad F, Humanski P, Piulats JM, Gonzalez Mella P, Ng SS, Jaeger D, Parnis FX, Franke FA, Puente J, Carvajal R, Sengeløv L, McHenry MB, Varma A, van den Eertwegh AJ, Gerritsen W. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017 Jan;35(1):40-47. Epub 2016 Oct 31. link to original article PubMed NCT01057810
  12. PROSPECT: Gulley JL, Borre M, Vogelzang NJ, Ng S, Agarwal N, Parker CC, Pook DW, Rathenborg P, Flaig TW, Carles J, Saad F, Shore ND, Chen L, Heery CR, Gerritsen WR, Priou F, Langkilde NC, Novikov A, Kantoff PW. Phase III trial of PROSTVAC in asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. J Clin Oncol. 2019 May 1;37(13):1051-1061. Epub 2019 Feb 28. link to original article link to PMC article PubMed NCT01322490