Novel Androgen Receptor Inhibitors in Non-Metastatic, Castration-Resistant Prostate Cancer: A Systematic Review and Network Meta-Analysis

INTRODUCTION: Enzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications. METHODS: PubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies. RESULTS: Three eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66–0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50–0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0–1.7) and serious AEs (OR, 1.3; 95% CI, 0.99–1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5–3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1–2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4–2.7) and serious AEs (OR, 1.9; 95% CI, 1.3–2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies. CONCLUSIONS: SGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.