Network meta-analysis (NMA) comparing the efficacy of enzalutamide versus apalutamide, darolutamide, and bicalutamide for treatment of nonmetastatic (nm) castration-resistant prostate cancer (CRPC).

101 Background: Enzalutamide is a potent androgen receptor (AR) inhibitor, targeting multiple steps in AR signaling. In recent years, the EMA and FDA approved enzalutamide for the management of adults with CRPC, irrespective of metastatic status, based on the Phase 3 PROSPER clinical trial results. To provide indirect evidence on the relative efficacy of enzalutamide vs bicalutamide or the second-generation AR antagonists apalutamide and darolutamide for the management of nmCRPC, a NMA was performed using published data from their Phase 3 clinical trials. Methods: NMA enables indirect comparison of ≥3 interventions across a network of studies, identified by systematic literature review and based on a common comparator, to estimate relative effects between interventions. This NMA compared data from PROSPER (enzalutamide vs placebo [PBO]), SPARTAN (apalutamide vs PBO), ARAMIS (darolutamide vs PBO), and STRIVE (enzalutamide vs bicalutamide) studies, following NICE technical support document 2. Four key endpoints (metastasis-free survival [MFS], overall survival [OS], time to prostate-specific antigen progression [TTPP], and time to first use of cytotoxic chemotherapy [TTCH]) were assessed. It was assumed that there was no variation between studies that could influence the size of treatment effect. Fixed-effect models were developed and implemented under a Bayesian framework. Results: MFS, OS, and TTCH outcomes of PROSPER, SPARTAN, and ARAMIS were compared between androgen deprivation treatment alone and in combination with enzalutamide/apalutamide/darolutamide. TTPP of PROSPER, SPARTAN, ARAMIS, and STRIVE was compared between enzalutamide, apalutamide, darolutamide, bicalutamide, and PBO. Enzalutamide showed significant benefit vs PBO for all endpoints measured (median hazard ratio [HR] 0.29, 0.73, 0.54, 0.07 for MFS, OS, TTCH, TTPP respectively, Table), vs darolutamide for MFS HR 0.71, and vs darolutamide HR 0.51 and bicalutamide HR 0.18 for TTPP. OS for enzalutamide vs apalutamide was not statistically different HR 0.94. Conclusions: Enzalutamide showed significant therapeutic benefit; MFS, OS, TTCH, and TTPP were better vs PBO and MFS and/or TTPP were longer compared to darolutamide and bicalutamide. No statistically significant differences were observed between enzalutamide and apalutamide. This NMA may facilitate the development and testing of treatment strategies for nmCRPC. [Table: see text]