Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77-0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78-0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69-0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74-0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Centre Montreal Canada

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Deaprtment of Urology PRES Centre Val de Loire CHRU Tours France Université François Rabelais de Tours Tours France

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Institute for Urology and Reproductive Health Sechenov University Moscow Russia Division of Urology Department of Special Surgery The University of Jordan Amman Jordan Department of Urology Weill Cornell Medical College New York NY USA Department of Urology University of Texas Southwestern Dallas TX USA Karl Landsteiner Institute of Urology and Andrology Vienna Austria Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic European Association of Urology Research Foundation Arnhem Netherlands

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

Department of Urology The Jikei University School of Medicine Tokyo Japan

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