OBJECTIVES : For nonmetastatic castration-resistant prostate cancer (nmCRPC), three drugs under patent protection—apalutamide, enzalutamide, and darolutamide—were approved based on randomized, placebo-controlled trials; one drug with generic availability—abiraterone acetate—showed promise in a single-arm trial (IMAAGEN). The comparative efficacy and safety of these products for nmCRPC are unclear.

METHODS : We conducted a systematic review and network meta-analysis of nmCRPC trials. We searched bibliographic databases, regulatory documents, and trial registries from inception through November 5, 2020 (PROSPERO CRD42020160839). We included patient-level data from two trials, IMAAGEN and STRIVE, and published aggregate data from other eligible trials. We employed matching-adjusted indirect comparison and Bayesian network meta-analysis to compare treatments by their benefits on metastasis-free survival (MFS), overall survival (OS), and their risks regarding serious adverse events (SAE).

RESULTS : Of six trials identified, five trials, with 4,360 participants in total, were eligible for analysis. Compared with placebo, abiraterone acetate was associated with the greatest benefit on MFS (hazard ratio [95% credible interval] 0·22 [0·12-0·41]), followed by apalutamide (0·28 [0·23-0·34]), enzalutamide (0·30 [0·25-0·36]), darolutamide (0·41 [0·34-0·49]); darolutamide was associated with the greatest benefit on OS (0·69 [0·53-0·90]), followed by enzalutamide (0·73 [0·61-0·87] and apalutamide (0·75 [0·59-0·95])—OS benefit not examined for abiraterone acetate; darolutamide was associated with the lowest risk of SAEs (odds ratio 1·32 [1·02-1·70]), followed by enzalutamide (1·43 [1·08-1·89]), apalutamide (1·58 [1·23-2·03]), and abiraterone acetate (1·94 [1·17-3·22]).

CONCLUSIONS : Among approved drugs for nmCRPC, darolutamide was associated with optimal efficacy and safety. Abiraterone acetate, currently indicated for metastatic prostate cancer, offered nmCRPC patients MFS benefit comparable to approved treatments, with cost-savings from its generic availability. Future research is needed to examine abiraterone acetate's OS benefit.