Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis.

Abstract

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.

• Authors: Keiichiro Mori, Hadi Mostafaei, Benjamin Pradere, Reza Sari Motlagh, Fahad Quhal, Ekaterina Laukhtina, Victor M Schuettfort, Mohammad Abufaraj, Pierre I Karakiewicz, Takahiro Kimura, Shin Egawa, Shahrokh F Shariat
• Journal: International journal of clinical oncology (Int J Clin Oncol) Vol. 25 Issue 11 Pg. 1892-1900 (Nov 2020) ISSN: 1437-7772 [Electronic] Japan
• PMID: 32924096 (Publication Type: Journal Article, Meta-Analysis, Systematic Review)

Chemical References

• Androgen Receptor Antagonists
• Antineoplastic Agents
• Benzamides
• Nitriles
• Pyrazoles
• Thiohydantoins
• apalutamide
• darolutamide
• Phenylthiohydantoin
• enzalutamide
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Androgen Receptor Antagonists (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Benzamides
• Humans
• Kallikreins (metabolism)
• Male
• Network Meta-Analysis
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, therapeutic use)
• Progression-Free Survival
• Proportional Hazards Models
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, mortality, pathology)
• Pyrazoles (therapeutic use)
• Thiohydantoins (therapeutic use)
• Treatment Outcome