Metastatic CRPC: Contemporary Therapeutic Options and Optimal Sequencing
Abstract
Prostate cancer (PC) is the most common malignancy among men worldwide. In Canada, an estimated 27,900 new diagnoses were projected in 2024, accounting for approximately 22% of all new cancer cases, with nearly 5,000 related deaths, making PC the fifth leading cause of cancer mortality. Approximately 8% of patients present with metastatic disease at diagnosis. Moreover, rates of de novo metastatic PC have increased in recent years, likely reflecting both the widespread adoption of advanced imaging modalities and reduced systematic screening practices.
Initial treatment for recurrent or de novo metastatic castration-sensitive prostate cancer (mCSPC) typically consists of androgen-deprivation therapy (ADT) combined with an androgen receptor pathway inhibitor (ARPI). In patients with high-volume disease, which is defined as ≥4 bone metastases (including ≥1 outside the vertebral column) or the presence of visceral metastases, triplet therapy with ADT, an ARPI, and docetaxel chemotherapy may be employed. In contrast, biochemical recurrence without radiographic metastases is generally managed with ADT alone, with treatment intensification using enzalutamide for patients with a prostate-specific antigen (PSA) doubling time between 3 and 9 months, as supported by the EMBARK trial.
References
Brenner DR, Gillis J, Demers AA, Ellison LF, Billette JM, Zhang SX, et al. Projected estimates of cancer in Canada in 2024. CMAJ. 2024;196(18):E615-23. https://doi.org/10.1503/cmaj.240095
Canadian Cancer Society. Cancer statistics [Internet]. Toronto (ON): Canadian Cancer Society; [cited 2026 Jan 7]. Available from: https://cancer.ca/en/research/cancer-statistics
Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. https://doi.org/10.3322/caac.21871
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-46. https://doi.org/10.1056/nejmoa1503747
Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-42. https://doi.org/10.1056/nejmoa2119115
Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Flechon A, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022;399(10336):1695-707. https://doi.org/10.1016/S0140-6736(22)00367-1
Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-65. https://doi.org/10.1056/NEJMoa2303974
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180-92. https://doi.org/10.1111/J.1742-1241.2011.02799.X
Saad F, So AI, Aprikian A, Finelli A, Fleshner NE, Gleave ME, et al. 2025 Canadian Urological Association-Canadian Uro-oncology Group Guideline: Metastatic castration-resistant prostate cancer (Update). Can Urol Assoc J. 2025;19(8):E276-E89. https://doi.org/10.5489/cuaj.9341
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2026. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed December 12th 2025.
Cai C, Balk SP. Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer. 2011;18(5):R175-82. https://doi.org/10.1530/ERC-10-0339
Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part II: Treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71(4):630-42. https://doi.org/10.1016/j.eururo.2016.08.002
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-18. https://doi.org/10.1200/JCO.2015.64.2702
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. https://doi.org/10.1056/NEJMoa1014618
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-48. https://doi.org/10.1056/NEJMoa1209096
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-97. https://doi.org/0.1056/NEJMoa1207506
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-33. https://doi.org/10.1056/NEJMoa1405095
Armstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, et al. Five-year survival prediction and safety outcomes with enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer from the PREVAIL trial. Eur Urol. 2020;78(3):347-57. https://doi.org/10.1016/j.eururo.2020.04.061
Sternberg CN, Fizazi K, Saad F, Shore ND, De Giorgi U, Penson DF, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-206. https://doi.org/10.1056/NEJMoa2003892
Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-18. https://doi.org/10.1056/NEJMoa1715546
Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-46. https://doi.org/10.1056/NEJMoa1815671
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12. https://doi.org/10.1056/NEJMOA040720
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-54. https://doi.org/10.1016/S0140-6736(10)61389-X
Eisenberger M, Hardy-Bessard AC, Kim CS, Geczi L, Ford D, Mourey L, et al. 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;35(28):3198-206. https://doi.org/10.1200/JCO.2016.72.1076
de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wulfing C, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-18. https://doi.org/10.1056/NEJMoa1911206
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-53. https://doi.org/10.1056/NEJMoa1603144
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-28. https://doi.org/10.1016/j.cell.2015.05.001
Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;2017. https://doi.org/10.1200/PO.17.00029
Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471-8. https://doi.org/10.1001/JAMAONCOL.2018.5801
de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-102. https://doi.org/10.1056/NEJMoa1911440
Saad F, Clarke NW, Oya M, Shore N, Procopio G, Guedes JD, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-108. https://doi.org/10.1016/S1470-2045(23)00382-0
Chi KN, Sandhu S, Smith MR, Attard G, Saad M, Olmos D, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-82. https://doi.org/10.1016/j.annonc.2023.06.009
Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402(10398):291-303. https://doi.org/10.1016/S0140-6736(23)01055-3
Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-103. https://doi.org/10.1056/NEJMOA2107322
Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. (177)Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-39. https://doi.org/10.1016/S0140-6736(24)01653-2
Sartor O, Jiang DM, Smoragiewicz M, Zibelman M, Flechon A, El-Haddad G, et al. Efficacy of ¹⁷⁷Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (SPLASH). Presented at: European Society for Medical Oncology (ESMO) Congress 2024; 13-17 September 2024; Barcelona, Spain. Abstract LBA65.
Graham LS, Montgomery B, Cheng HH, Yu EY, Nelson PS, Pritchard C, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. https://doi.org/10.1371/JOURNAL.PONE.0233260
Graff JN, Burotto M, Fong PC, Pook DW, Zurawski B, Manneh Kopp R, et al. Pembrolizumab plus enzalutamide versus placebo plus enzalutamide for chemotherapy-naive metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-641 study. Ann Oncol. 2025;36(8):976-87. https://doi.org/10.1016/j.annonc.2025.05.007
Petrylak DP, Ratta R, Matsubara N, Korbenfeld E, Gafanov R, Mourey L, et al. Pembrolizumab plus docetaxel versus docetaxel for previously treated metastatic castration-resistant prostate cancer: the randomized, double-blind, phase III KEYNOTE-921 trial. J Clin Oncol. 2025;43(14):1638-49. https://doi.org/10.1200/JCO-24-01283
Antonarakis ES, Park SH, Goh JC, Shin SJ, Lee JL, Mehra N, et al. Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: the randomized, open-label, phase III KEYLYNK-010 trial. J Clin Oncol. 2023;41(22):3839-50. https://doi.org/10.1200/JCO.23.00233
Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-23. https://doi.org/10.1056/NEJMoa1213755
Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002;168(6):2439-43. https://doi.org/10.1016/S0022-5347(05)64163-8
Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. 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;14(6):1756-64. https://doi.org/10.1200/JCO.1996.14.6.1756
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22. https://doi.org/10.1056/NEJMoa1001294
Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-82. https://doi.org/10.1093/jnci/djh141
Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745-55. https://doi.org/10.1056/NEJMoa0809003
Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-22. https://doi.org/10.1016/S0140-6736(10)62344-6
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Canadian Oncology Today
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
