Updated treatment recommendations for prostate cancer from the ESMO Clinical Practice Guideline considering treatment intensification and use of novel systemic agents

•Abiraterone acetate with prednisone improved MFS and OS for patients with very-high-risk localised prostate cancer undergoing RT and ADT.•Combining ADT with docetaxel -abiraterone -prednisone in men with de novo mHSPC improved both rPFS and OS versus ADT -docetaxel.•Combining ADT with docetaxel and darolutamide in men with mHSPC improved OS versus ADT -docetaxel.•Olaparib improved OS in men with mCRPC and BRCA alterations post-novel androgen receptor axis inhibitor.•Cabazitaxel in men with mCRPC post-novel androgen receptor axis inhibitor and docetaxel improved both rPFS and OS.•177Lu-PSMA-617 in men with mCRPC post-novel androgen receptor axis inhibitor and taxanes improved both rPFS and OS. The following ESMO Clinical Practice Guideline has been recently updated with new treatment recommendations: Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.1Parker C. Castro E. Fizazi K. et al.Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2020; 31: 1119-1134Google Scholar View the ESMO eUpdate here: https://www.esmo.org/guidelines/genitourinary-cancers/prostate-cancer/eupdate-prostate-cancer-treatment-recommendations. In the updated analysis of the STAMPEDE phase III trial, 2 years of abiraterone–prednisone improved both metastases-free survival (MFS) [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.43-0.68, P = 3.2 × 10−7] and overall survival (OS) (HR 0.63, 95% CI 0.48-0.82, P = 0.0005) in men with very high-risk M0 prostate cancer [defined by N1 disease or at least two risk factors among T3-T4, prostate-specific antigen (PSA) >40 ng/ml, Gleason score 8-10].2Attard G. Murphy L. Clarke N.W. et al.Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.Lancet. 2022; 399: 447-460Google Scholar In the PEACE-1 phase III trial, adding abiraterone–prednisone to androgen deprivation therapy (ADT) plus docetaxel improved both radiographic progression-free survival (rPFS) (HR 0.50, 99.9% CI 0.34-0.71, P < 0.0001) and OS (HR 0.75, 95.1% CI 0.59-0.95, P = 0.017). In the ‘high-volume’ population (men with at least four bone metastases, including at least one in the peripheral skeleton, or visceral metastases), survival medians were reached: 5.14 years with abiraterone–ADT–docetaxel versus 3.47 years (3.2-4.0 years) with ADT–docetaxel (HR 0.72, 95.1% CI 0.55-0.95, P = 0.019).3Fizazi K. Foulon S. Carles J. 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 × 2 factorial design.Lancet. 2022; 399: 1695-1707Google Scholar Similarly, the ARASENS phase III trial showed that adding darolutamide to ADT plus docetaxel improved OS (HR 0.68, 95% CI 0.57-0.80, P < 0.0001). No data on rPFS or by burden of disease are currently available.4Smith M.R. Hussain M. Saad F. et al.Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.N Engl J Med. 2022; 386: 1132-1142Google Scholar In the updated analysis of the PROfound trial testing olaparib versus a second androgen receptor axis inhibitor in men with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 or ATM, and whose disease had progressed on prior androgen receptor axis inhibitor (and docetaxel in some patients), OS was significantly improved in olaparib-treated patients: HR 0.69, 95% CI 0.50-0.97, P = 0.0175; medians: 19.1 versus 14.7 months. The benefit was predominantly observed in men with BRCA alterations.5Hussain M. Mateo J. Fizazi K. et al.Survival with olaparib in metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 383: 2345-2357Google Scholar In the CARD trial, cabazitaxel improved both rPFS (HR 0.54, 95% CI 0.40-0.73, P < 0.001; medians: 8.0 versus 3.7 months) and OS (HR 0.64, 95% CI 0.46-0.89, P = 0.008; medians: 13.6 versus 11.0 months) compared with abiraterone or enzalutamide in men with mCRPC pretreated with docetaxel and who had progression within 12 months while receiving a novel androgen receptor axis inhibitor.6de Wit R. de Bono J. Sternberg C.N. et al.Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer.N Engl J Med. 2019; 381: 2506-2518Google Scholar In the VISION trial, combining lutetium-177 prostate-specific membrane antigen (177Lu-PSMA-617) with best standard of care improved both rPFS (HR 0.40, 99.2% CI 0.29-0.57, P < 0.001; medians: 8.7 versus 3.4 months) and OS (HR 0.62, 95% CI 0.52-0.74, P < 0.001; medians: 15.3 versus 11.3 months) compared with best standard of care only in men with mCRPC pretreated with at least one taxane and at least one novel androgen receptor axis inhibitor.7Sartor O. de Bono J. Chi K.N. et al.Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer.N Engl J Med. 2021; 385: 1091-1103Google Scholar •External beam radiotherapy (RT) plus ADT–abiraterone–prednisone is recommended for men with very high-risk M0 prostate cancer (defined by N1 disease or at least two risk factors among T3-T4, PSA >40 ng/ml, Gleason score 8-10) [I, B; not European Medicines Agency (EMA) or Food and Drug Administration (FDA) approved for use in M0 disease].•Men receiving radical RT for very high-risk disease should have long-course ADT (24-36 months) plus abiraterone–prednisone (24 months) [I, B].•ADT–docetaxel–abiraterone–prednisone is recommended as first-line treatment for fit men with de novo metastatic hormone-sensitive prostate cancer (mHSPC), especially in those with multiple bone metastases (>3) or visceral metastases [I, B; European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 4; regimen not EMA or FDA approved]. ADT–docetaxel–darolutamide is also recommended as first-line treatment of mHSPC, including patients with de novo mHSPC and those who have progressed to metastatic disease [I, B; ESMO-MCBS v1.1 score: 4].•The other treatment option for men with mHSPC is a novel hormone agent (NHA) plus ADT [ADT–abiraterone–prednisone (ESMO-MCBS v1.1 score: 4), ADT–apalutamide (ESMO-MCBS v1.1 score: 4) or ADT–enzalutamide (ESMO-MCBS v1.1 score: 4)], which is recommended for first-line treatment [I, A]. Both strategies (NHA–ADT versus triplet therapy) have not been directly compared.•In men with mHSPC, ADT alone should be used only in vulnerable men who cannot tolerate treatment intensification [III, C].•Olaparib should be considered after novel androgen receptor axis inhibitors (with or without prior taxane treatment) for patients with mCRPC and BRCA1/2 alterations [I, B; ESMO-MCBS v1.1 score: 3].•In patients with mCRPC who have received a novel androgen receptor axis inhibitor (abiraterone, apalutamide, darolutamide or enzalutamide) and docetaxel, the following treatments should be used in patients who are considered fit enough to receive these treatments:o177Lu-PSMA-617 in men with cancer expressing PSMA on positron emission tomography-PSMA and without PSMA non-expressing lesions [I, A; ESMO-MCBS v1.1 score: 4].oCabazitaxel [I, A; ESMO-MCBS v1.1 score: 3]. An ESMO-MCBS table with ESMO-MCBS scores is included in Table 1. ESMO-MCBS v1.18Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Google Scholar was used to calculate scores for new therapies/indications approved by the EMA or FDA (https://www.esmo.org/Guidelines/ESMO-MCBS). The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. The FDA/EMA or other regulatory body approval status of new therapies/indications is reported at the time of writing this eUpdate.Table 1ESMO-MCBS table for therapies/indications in prostate cancerTherapyDisease settingTrialControlAbsolute survival gainHR (95% CI)QoL/toxicityESMO-MCBS scoreaThe scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ESMO-MCBS v1.18 was used to calculate scores https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms.mHSPCAbiraterone–prednisone–ADTNewly diagnosed high-risk mHSPC in patients in combination with ADTSTAMPEDE9James N.D. de Bono J.S. Spears M.R. et al.Abiraterone for prostate cancer not previously treated with hormone therapy.N Engl J Med. 2017; 377: 338-351Google Scholar,10James N.D. Clarke N.W. Cook A. et al.Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).Int J Cancer. 2022; 151: 422-434Google ScholarPhase II/IIINCT00268476Placebo–ADTMedian OS: 46 monthsOS gain: 33 monthsOS: 0.60 (0.50-0.71)QoL data pending4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Abiraterone–prednisone–ADTNewly diagnosed high-risk mHSPC in patients in combination with ADTLATITUDE11Fizazi K. Tran N. Fein L. et al.Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med. 2017; 377: 352-360Google Scholar, 12Fizazi K. Tran N. Fein L. et al.Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial.Lancet Oncol. 2019; 20: 686-700Google Scholar, 13Chi K.N. Protheroe A. Rodríguez-Antolín A. et al.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; 19: 194-206Google ScholarPhase IIINCT01715285Placebo–ADTMedian OS: 36.5 monthsMedian PFS: 14.8 monthsOS gain: 16.8 monthsPFS gain: 18.2 monthsOS: 0.66 (0.56-0.78)PFS: 0.47 (0.39-0.55)QoL was not a secondary endpoint4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Abiraterone–ADT ± docetaxel ± RTcNot EMA or FDA approved.Overall populationDe novo mHSPCPEACE-13Fizazi K. Foulon S. Carles J. 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 × 2 factorial design.Lancet. 2022; 399: 1695-1707Google ScholarPhase IIINCT01957436ADT ± docetaxel ± RTMedian rPFS: 2.2 yearsMedian OS: 4.7 yearsrPFS gain: 2.3 yearsOS gain: 1 yearrPFS: 0.54 (0.41-0.71)d99.9% CI of the rPFS HR.OS: 0.82 (0.69-0.98)QoL data pending4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Abiraterone–ADT–docetaxel ± RTcNot EMA or FDA approved.ADT with docetaxel populationDe novo mHSPCPEACE-13Fizazi K. Foulon S. Carles J. 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 × 2 factorial design.Lancet. 2022; 399: 1695-1707Google ScholarPhase IIINCT01957436ADT–docetaxel ± RTMedian rPFS: 2.0 yearsMedian OS: 4.4 yearsrPFS gain: 2.5 yearsOS gain: 1.5 yearseCalculated estimate of gain based on PE HR 0.75.rPFS: 0.50 (0.34-0.71)d99.9% CI of the rPFS HR.OS: 0.75 (0.59-0.95)QoL data pending4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Apalutamide–ADTmHSPC in combination with ADTTITAN14Agarwal N. McQuarrie K. Bjartell A. et al.Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study.Lancet Oncol. 2019; 20: 1518-1530Google Scholar, 15Chi K.N. Agarwal N. Bjartell A. et al.Apalutamide for metastatic, castration-sensitive prostate cancer.N Engl J Med. 2019; 381: 13-24Google Scholar, 16Chi K.N. Chowdhury S. Bjartell A. et al.Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, Phase III TITAN study.J Clin Oncol. 2021; 39: 2294-2303Google ScholarPhase IIINCT02489318Placebo–ADTMedian PFS: 22.1 monthsMedian OS: 52.2 monthsPFS gain: 23.9 monthsfCalculated estimate of gain based on PE HR 0.48.OS gain: 28.1 monthsgCalculated estimate of gain based on PE HR 0.65.PFS: 0.48 (0.39-0.60)OS: 0.65 (0.53-0.79)No QoL benefitIschaemic heart disease 4.4% versus 1.5%4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Darolutamide–docetaxel–ADTFor adult men with mHSPCARASENS4Smith M.R. Hussain M. Saad F. et al.Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.N Engl J Med. 2022; 386: 1132-1142Google ScholarPhase IIINCT02799602Docetaxel–ADTMedian OS: 48.9 monthsOS gain: 23.0 monthshCalculated estimate of gain based on PE HR 0.68.OS: 0.68 (0.57-0.80)QoL was not a prespecified endpoint4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2a)Docetaxel–ADTiEMA approved, not FDA approved in mHSPC.Metastatic and high-risk locally advancedIn combination with ADT, with or without prednisone or prednisolone, for the treatment of patients with mHSPCSTAMPEDE17James N.D. Sydes M.R. Clarke N.W. et al.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; 387: 1163-1177Google ScholarPhase II/IIINCT00268476ADTMedian OS: 71.0 monthsOS gain: 10.0 monthsOS: 0.78 (0.66-0.93)QoL data pending4 (Form 2a)Docetaxel–ADTiEMA approved, not FDA approved in mHSPC.In combination with ADT, with or without prednisone or prednisolone, for the treatment of patients with mHSPCCHAARTED18Kyriakopoulos C.E. Chen Y.H. Carducci M.A. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial.J Clin Oncol. 2018; 36: 1080-1087Google Scholar, 19Morgans A.K. Chen Y.H. Sweeney C.J. et al.Quality of life during treatment with chemohormonal therapy: analysis of E3805 chemohormonal androgen ablation randomized trial in prostate cancer.J Clin Oncol. 2018; 36: 1088-1095Google Scholar, 20Sweeney C.J. Chen Y.H. Carducci M. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-746Google ScholarPhase IIINCT00309985ADTITT median OS: 47.2 monthsITT OS gain: 10.4 monthsOS: 0.72 (0.59-0.89)QoL benefits were lower than the described threshold for significance4 (Form 2a)Docetaxel–ADTiEMA approved, not FDA approved in mHSPC.In combination with ADT, with or without prednisone or prednisolone, for the treatment of patients with mHSPCGETUG-1521Gravis G. Fizazi K. Joly F. et al.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; 14: 149-158Google ScholarPhase IIINCT00104715ADTMedian OS: 54.2 monthsOS gain: 4.7 monthsOS: 1.01 (0.75-1.36)No QoL benefitNo evaluable benefit (Form 2a)Enzalutamide–ADTFirst-line treatmentAdult men with mHSPC in combination with ADTENZAMET22Davis I.D. Martin A.J. Stockler M.R. et al.Enzalutamide with standard first-line therapy in metastatic prostate cancer.N Engl J Med. 2019; 381: 121-131Google Scholar,23Stockler M.R. Martin A.J. Davis I.D. et al.Health-related quality of life in metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 1304), an international, randomized phase III trial led by ANZUP.J Clin Oncol. 2022; 40: 837-846Google ScholarPhase IIINCT02446405ADTMedian PFS: 24.0 monthsjEstimated from Kaplan–Meier plot.3-year OS: 72%PFS gain: 36.0 monthskCalculated estimate of gain based on PE HR 0.40.3-year OS gain: 8%PFS: 0.40 (0.33-0.49)OS: 0.67 (0.52-0.86) interim OS (P = 0.002; <0.003 threshold for interim analysis)Improved QoL4bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2b)lForm 2a cannot be applied since median OS was not reached in the control arm; consequently, score was derived from Form 2b criteria with an upgrade for early stopping based on OS advantage detected at the interim analysis.Enzalutamide–ADTAdult men with mHSPC in combination with ADTARCHES24Armstrong A.J. Szmulewitz R.Z. Petrylak D.P. et al.ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.J Clin Oncol. 2019; 37: 2974-2986Google Scholar, 25Stenzl A. Dunshee C. De Giorgi U. et al.Effect of enzalutamide plus androgen deprivation therapy on health-related quality of life in patients with metastatic hormone-sensitive prostate cancer: an analysis of the ARCHES randomised, placebo-controlled, phase 3 study.Eur Urol. 2020; 78: 603-614Google Scholar, 26Armstrong A.J. Azad A.A. Iguchi T. et al.Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer.J Clin Oncol. 2022; 40: 1616-1622Google ScholarPhase IIINCT02677896Placebo–ADTMedian PFS: 38.9 months4-year OS: 57%PFS gain: 10.9 months4-year OS gain: 14%PFS: 0.63 (0.52-0.76)OS: 0.66 (0.53-0.81)No QoL benefit3bOS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant. (Form 2b)RelugolixAdult patients with advanced HSPCHERO27Shore N.D. Saad F. Cookson M.S. et al.Oral relugolix for androgen-deprivation therapy in advanced prostate cancer.N Engl J Med. 2020; 382: 2187-2196Google ScholarPhase IIINCT03085095LeuprolideNon-inferior and superior castration rateBetween-group difference: 7.9% (95% CI 4.1% to 11.8%)QoL data pendingReduced toxicitySignificantly lower risk of major CV events (HR 0.46, 95% CI 0.24-0.88)4 (Form 2c)nmCRPCApalutamide–ADTAdult men with nmCRPC who are at high risk of developing metastatic diseaseSPARTAN28Saad F. Cella D. Basch E. et al.Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2018; 19: 1404-1416Google Scholar, 29Smith M.R. Saad F. Chowdhury S. et al.Apalutamide treatment and metastasis-free survival in prostate cancer.N Engl J Med. 2018; 378: 1408-1418Google Scholar, 30Smith M.R. Saad F. Chowdhury S. et al.Apalutamide and overall survival in prostate cancer.Eur Urol. 2021; 79: 150-158Google Scholar, 31Small E.J. Saad F. Chowdhury S. et al.Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.Ann Oncol. 2019; 30: 1813-1820Google ScholarPhase IIINCT01946204Placebo–ADTMedian MFS: 16.2 monthsMedian OS: 59.9 monthsMFS gain: 24.3 monthsMedian OS gain: 14.0 monthsMFS: 0.28 (0.23-0.35)OS: 0.78 (0.64-0.96)QoL was an exploratory endpoint4 (Form 2a)Darolutamide–ADTAdult men with nmCRPC who are at high risk of developing metastatic diseaseARAMIS32Fizazi K. Shore N. Tammela T.L. et al.Darolutamide in nonmetastatic, castration-resistant prostate cancer.N Engl J Med. 2019; 380: 1235-1246Google Scholar,33Fizazi K. Shore N. Tammela T.L. et al.Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide.N Engl J Med. 2020; 383: 1040-1049Google ScholarPhase IIINCT02200614Placebo–ADTMedian MFS: 18.4 months3-year OS: 77%MFS gain: 22.0 months3-year OS gain: 6%MFS: 0.41 (0.34-0.50)OS: 0.69 (0.53-0.88)QoL was not a prespecified secondary endpoint3 (Form 2b)Enzalutamide–ADTAdult men with high-risk nmCRPCPROSPER34Hussain M. Fizazi K. Saad F. et al.Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.N Engl J Med. 2018; 378: 2465-2474Google Scholar, 35Sternberg C.N. Fizazi K. Saad F. et al.Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer.N Engl J Med. 2020; 382: 2197-2206Google Scholar, 36Tombal B. Saad F. Penson D. et al.Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial.Lancet Oncol. 2019; 20: 556-569Google ScholarPhase IIINCT02003924Placebo–ADTMedian MFS: 14.7 monthsMedian OS: 56.3 monthsMFS gain: 21.9 monthsOS gain: 10.7 monthsMFS: 0.29 (0.24-0.35)OS: 0.73 (0.61-0.89)No improvement in global QoL4 (Form 2a)mCRPC177Lu-PSMA-617 + best standard of care (restricted)Adult patients with progressive PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based ChTVISION7Sartor O. de Bono J. Chi K.N. et al.Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer.N Engl J Med. 2021; 385: 1091-1103Google ScholarPhase IIINCT03511664Best standard of care (restricted)Median OS: 11.3 monthsOS gain: 4.0 monthsOS: 0.62 (0.52-0.74)QoL data pendingDeteriorated toxicity (based on grade ≥3 AEs): 52.7% versus 38%4mSubstandard control arm: precluded cabazitaxel. (Form 2a)Abiraterone–prednisonemCRPC in adult men whose disease has progressed on or after a docetaxel-based ChT regimenCOU-AA-30137de Bono J.S. Logothetis C.J. Molina A. et al.Abiraterone and increased survival in metastatic prostate cancer.N Engl J Med. 2011; 364: 1995-2005Google Scholar, 38Fizazi K. Scher H.I. Molina A. et al.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; 13: 983-992Google Scholar, 39Harland S. Staffurth J. Molina A. et al.Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy.Eur J Cancer. 2013; 49: 3648-3657Google ScholarPhase IIINCT00638690Placebo–prednisoneMedian OS: 11.2 monthsOS gain: 4.6 monthsOS: 0.74 (0.64-0.86)QoL was an exploratory endpoint4 (Form 2a)Abiraterone–prednisonenFDA approved, not EMA approved in ChT-naïve patients with mCRPC.ChT-naïve men with mCRPCPatients with mCRPCCOU-AA-30240Ryan C.J. Smith M.R. de Bono J.S. et al.Abiraterone in metastatic prostate cancer without previous chemotherapy.N Engl J Med. 2013; 368: 138-148Google Scholar, 41Ryan C.J. Smith M.R. Fizazi K. et al.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; 16: 152-160Google Scholar, 42Basch E. Autio K. Ryan C.J. et al.Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial.Lancet Oncol. 2013; 14: 1193-1199Google ScholarPhase IIINCT00887198Placebo–prednisoneMedian OS: 30.3 monthsOS gain: 4.4 monthsOS: 0.81 (0.70-0.93)QoL was not a secondary endpoint2 (Form 2a)Cabazitaxel + prednisone or prednisoloneAfter docetaxelIn combination with prednisone or prednisolone for the treatment of adult patients with mCRPC previously treated with a docetaxel-containing regimenTROPIC43de Bono J.S. Oudard S. Ozguroglu M. 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: 1147-1154Google ScholarPhase IIINCT00417079Mitoxantrone–prednisoneMedian OS: 12.7 monthsOS gain: 2.4 monthsOS: 0.70 (0.59-0.83)QoL was not a secondary endpoint2 (Form 2a)Cabazitaxel + prednisone or prednisoloneAfter docetaxel and AST inhibitorIn combination with prednisone or prednisolone for the treatment of adult patients with mCRPC previously treated with a docetaxel-containing regimenCARD6de Wit R. de Bono J. Sternberg C.N. et al.Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer.N Engl J Med. 2019; 381: 2506-2518Google Scholar,44Fizazi K. Kramer G. Eymard J.C. et al.Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study.Lancet Oncol. 2020; 21: 1513-1525Google ScholarPhase IVNCT02485691Abiraterone or enzalutamide (alternative to previously used)Median PFS: 3.7 monthsMedian OS: 11.0 monthsPFS gain: 4.3 monthsOS gain: 2.6 monthsPFS: 0.54 (0.40-0.73)OS: 0.64 (0.46-0.89)Single symptom improvement not eligible for global QoL upgrade3 (Form 2a)Docetaxel q3wIn combination with prednisone or prednisolone for the treatment of patients with mCRPCTAX 32745Tannock I.F. de Wit R. Berry W.R. et al.Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.N Engl J Med. 2004; 351: 1502-1512Google Scholar,46Berthold D.R. Pond G.R. Soban F. et al.Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study.J Clin Oncol. 2008; 26: 242-245Google ScholarPhase IIIMitoxantrone–prednisoneMedian OS: 16.3 monthsOS gain: 2.9 monthsOS: 0.79 (0.67-0.93)Improved QoL3 (Form 2a)EnzalutamideAdult men with mCRPC who are asymptomatic or mildly symptomatic after failure of ADT in whom ChT is not yet clinically indicatedPREVAIL47Beer T.M. Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy.N Engl J Med. 2014; 371: 1755-1756Google Scholar,48Loriot Y. Miller K. Sternberg C.N. et al.Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.Lancet Oncol. 2015; 16: 509-521Google ScholarPhase IIINCT01212991PlaceboMedian PFS: 3.9 monthsMedian OS: 30.2 monthsPFS gain: >12 monthsOS gain: 2.2 monthsPFS: 0.19 (0.15-0.23)OS: 0.71 (0.60-0.84)QoL was an exploratory endpoint4 (Form 2b)lForm 2a cannot be applied since median OS was not reached in the control arm; consequently, score was derived from Form 2b criteria with an upgrade for early stopping based on OS advantage detected at the interim analysis.EnzalutamideAdult men with mCRPC whose disease has progressed on or after docetaxel therapyAFFIRM49Cella D. Ivanescu C. Holmstrom S. et al.Impact of enzalutamide on quality of life in men with metastatic castration-resistant prostate cancer after chemotherapy: additional analyses from the AFFIRM randomized clinical trial.Ann Oncol. 2015; 26: 179-185Google Scholar,50Scher H.I. Fizazi K. Saad F. et al.Increased survival with enzalutamide in prostate cancer after chemotherapy.N Engl J Med. 2012; 367: 1187-1197Google ScholarPhase IIINCT00974311PlaceboMedian OS: 13.6 monthsOS gain: 4.8 monthsOS: 0.63 (0.53-0.75)QoL improved4 (Form 2a)OlaparibPatients with ≥1 alteration in BRCA1, BRCA2 or ATMAdult patients with mCRPC and BRCA1/2 mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agentPROfound5Hussain M. Mateo J. Fizazi K. et al.Survival with olaparib in metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 383: 2345-2357Google Scholar,51de Bono J. Mateo J. Fizazi K. et al.Olaparib for metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 382: 2091-2102Google Scholar,52Thiery-Vuillemin A. de Bono J. Hussain M. et al.Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial.Lancet Oncol. 2022; 23: 393-405Google ScholarPhase IIINCT02987543Enzalutamide or abiraterone (crossover allowed)Median PFS: 3.6 monthsMedian OS: 14.7 monthsPFS gain: 3.8 monthsOS gain: 4.4 monthsPFS: 0.34 (0.25-0.47)OS: 0.69 (0.50-0.97)No overall QoL benefit3 (Form 2b)OlapariboFDA approved, EMA approval is restricted to patients with germline and/or somatic BRCA1/2 mutations.Patients with ≥1 alteration in BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54LAdult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abirateronePROfound5Hussain M. Mateo J. Fizazi K. et al.Survival with olaparib in metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 383: 2345-2357Google Scholar,51de Bono J. Mateo J. Fizazi K. et al.Olaparib for metastatic castration-resistant prostate cancer.N Engl J Med. 2020; 382: 2091-2102Google ScholarPhase IIINCT02987543Enzalutamide or abiraterone (crossover allowed)Median OS: 11.5 monthsOS gain: 2.6 monthsOS: 0.96 (0.63-1.49)No overall QoL benefitNo evaluable benefit (Form 2a)Olaparib–abiraterone + prednisone or prednisolonepEMA approved, not FDA approved.Adult men with mCRPC in whom ChT is not clinically indicatedPROpel53Clarke N.W. Armstrong A.J. Thiery-Vuillemin A. et al.Abiraterone and olaparib for metastatic castration-resistant prostate cancer.NEJM Evidence. 2022; 1EVIDoa2200043Google ScholarPhase IIINCT03732820Placebo–abiraterone + prednisone or prednisoloneMedian PFS: 16.6 monthsPFS gain: 8.2 monthsPFS: 0.66 (0.54-0.81)OS: NS (immature)No QoL benefitPulmonary embolism: 6.5% versus 1.8%2 (Form 2b)Radium-223 + best standard of careAdult patients with mCRPC, symptomatic bone metastases and no known visceral metastases, in progression after ≥2 prior lines of systemic therapy for mCRPC (other than LHRH analogues), or ineligible for any available systemic mCRPC treatmentALSYMPCA54Parker C. Nilsson S. Heinrich D. et al.Alpha emitter radium-223 and survival in metastatic prostate cancer.N Engl J Med. 2013; 369: 213-223Google ScholarPhase IIINCT00699751Placebo + best standard of careMedian OS: 11.3 monthsOS gain: 3.6 monthsOS: 0.70 (0.58-0.83)QoL was an exploratory endpoint4 (Form 2a)RucaparibqFDA approved, not EMA approved.Adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based ChTTRITON255Abida W. Patnaik A. Campbell D. et al.Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration.J Clin Oncol. 2020; 38: 3763-3772Google ScholarPhase IINCT02952534Single armORR: 43.5%Median DoR: 6.4 monthsMedian PFS: 9.0 monthsQoL was not a prespecified endpoint3 (Form 3)177Lu, lutetium-177; ADT, androgen deprivation therapy; AE, adverse event; AST, androgen signalling-targeted; ChT, chemotherapy; CI, confidence interval; CRPC, castration-resistant prostate cancer; CV, cardiovascular; DoR, duration of response; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; HR, hazard ratio; HRR, homologous recombination repair; HSPC, hormone-sensitive prostate cancer; ITT, intention-to-treat; LHRH, luteinising hormone-releasing hormone; m, metastatic; MFS, metastasis-free survival; nm, non-metastatic; NS, not significant; ORR, overall response rate; OS, overall survival; PE, point estimate; PFS, progression-free survival; PSMA, prostate-specific membrane antigen; q3w, every 3 weeks; QoL, quality of life; rPFS, radiographic progression-free survival; RT, radiotherapy.a The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ESMO-MCBS v1.18Cherny N.I. Dafni U. Bogaerts J. et al.ESMO-magnitude of clinical benefit scale version 1.1.Ann Oncol. 2017; 28: 2340-2366Google Scholar was used to calculate scores https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms.b OS of the control arm may be overestimated by inadequate post-progression treatment of control arm patients with abiraterone or enzalutamide when castrate resistant.c Not EMA or FDA approved.d 99.9% CI of the rPFS HR.e Calculated estimate of gain based on PE HR 0.75.f Calculated estimate of gain based on PE HR 0.48.g Calculated estimate of gain based on PE HR 0.65.h Calculated estimate of gain based on PE HR 0.68.i EMA approved, not FDA approved in mHSPC.j Estimated from Kaplan–Meier plot.k Calculated estimate of gain based on PE HR 0.40.l Form 2a cannot be applied since median OS was not reached in the control arm; consequently, score was derived from Form 2b criteria with an upgrade for early stopping based on OS advantage detected at the interim analysis.m Substandard control arm: precluded cabazitaxel.n FDA approved, not EMA approved in ChT-naïve patients with mCRPC.o FDA approved, EMA approval is restricted to patients with germline and/or somatic BRCA1/2 mutations.p EMA approved, not FDA approved.q FDA approved, not EMA approved. Open table in a new tab 177Lu, lutetium-177; ADT, androgen deprivation therapy; AE, adverse event; AST, androgen signalling-targeted; ChT, chemotherapy; CI, confidence interval; CRPC, castration-resistant prostate cancer; CV, cardiovascular; DoR, duration of response; EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; HR, hazard ratio; HRR, homologous recombination repair; HSPC, hormone-sensitive prostate cancer; ITT, intention-to-treat; LHRH, luteinising hormone-releasing hormone; m, metastatic; MFS, metastasis-free survival; nm, non-metastatic; NS, not significant; ORR, overall response rate; OS, overall survival; PE, point estimate; PFS, progression-free survival; PSMA, prostate-specific membrane antigen; q3w, every 3 weeks; QoL, quality of life; rPFS, radiographic progression-free survival; RT, radiotherapy. The authors thank C. Parker, E. Castro, A. Heidenreich, P. Ost, G. Procopio and B. Tombal, authors of the ESMO Clinical Practice Guideline on Prostate Cancer,1Parker C. Castro E. Fizazi K. et al.Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2020; 31: 1119-1134Google Scholar for their review of this eUpdate. Manuscript editing support was provided by Louise Green, Jennifer Lamarre and Claire Bramley (ESMO Guidelines staff) and Angela Corstorphine of Kstorfin Medical Communications Ltd (KMC); this support was funded by ESMO. Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni, ESMO-MCBS Working Group Member/Frontier Science Foundation Hellas, and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scientific Affairs staff) provided coordination and support of the ESMO-MCBS scores and Angela Corstorphine and Sian-Marie Lucas of KMC provided medical writing and editing support in the preparation of the ESMO-MCBS table; this support was funded by ESMO. No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO from central funds.