The efficacy and adverse events of conventional and second-generation androgen receptor inhibitors for castration-resistant prostate cancer: A network meta-analysis

Background: Second-generation androgen receptor inhibitors (ARIs) have been developed and approved for treating castration-resistant prostate cancer (CRPC), but direct comparisons with the conventional ARI bicalutamide are limited. Methods: A Bayesian network meta-analysis of randomized controlled trials (RCTs) compared therapeutic efficacy and adverse events (AEs) among bicalutamide and second-generation ARIs (enzalutamide, apalutamide, darolutamide) in CRPC, using data from PubMed, Cochrane Library, and Embase through October 2022. Outcomes included progression-free survival (PFS), PSA progression-free survival (PSA-PFS), overall survival (OS), metastasis-free survival (MFS), PSA response rate, and safety endpoints; subgroup analyses were performed for non-metastatic (nmCRPC) and metastatic CRPC (mCRPC). Results: Seven RCTs with 6,993 participants were included. All three second-generation ARIs outperformed bicalutamide in efficacy, with darolutamide slightly less effective than enzalutamide and apalutamide. Overall AE rates were similar across ARIs; apalutamide showed slightly higher grade ≥3 AEs, AE-related discontinuations, and AE-related mortality. Enzalutamide was associated with higher risks of hypertension and fatigue. In subgroup analyses, enzalutamide was superior to bicalutamide in both nmCRPC and mCRPC; in nmCRPC, enzalutamide and apalutamide provided more benefit for PFS and PSA-PFS than darolutamide. Conclusion: Second-generation ARIs are superior to bicalutamide for CRPC. Enzalutamide and apalutamide show broadly similar efficacy, while darolutamide is slightly less effective; apalutamide may have a higher incidence of key AEs, though between-ARI differences were not statistically significant. All ARIs were generally well tolerated.

Xianlu Zhang, Gejun Zhang, Jianfeng Wang, Jianbin Bi, Xiaolan Deng, Yanlong Wang, Yinu Wang