Oral darolutamide therapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC): A systematic review and meta-analysis of phase III randomized controlled trials.

Abstract

e17095 Background: Prostate cancer (PCa) is one of the most common malignancies among men globally and remains a leading cause of cancer mortality. It is the second most prevalent solid tumor in men and the fifth most common cause of cancer-related deaths. Darolutamide is a next-generation nonsteroidal androgen receptor antagonist designed to have potent AR blockade with minimal CNS penetration. The study aims to assess the efficacy and safety of oral darolutamide therapy in men with hormone-sensitive prostate cancer. Methods: A comprehensive literature search was conducted across PubMed, Cochrane, Scopus, Embase, and ClinicalTrials.gov from inception to November 2025, selecting studies based on predefined eligibility criteria, following PRISMA guidelines. Time-to-event outcomes were pooled as Hazard Ratios (HR) with 95% confidence intervals (CI) using fixed-effect models for outcomes with low heterogeneity, and random-effects models to account for potential heterogeneity. Sensitivity analyses were also performed for outcomes with moderate to high heterogeneity. Heterogeneity was assessed using I² and X² statistics, with a p-value of < 0.05 considered statistically significant. All calculations were performed using RevMan 5.4. Results: A total of 13 Randomized Controlled trials were included in the study. Analysis demonstrated that darolutamide was associated with a statistically significant improvement in overall survival compared with control therapy (HR = 0.62, 95% CI 0.55–0.70; p < 0.00001). Funnel plot inspection did not reveal any marked asymmetry. It significantly prolonged the time to castration-resistant prostate cancer compared with control treatment (HR = 0.38, 95% CI 0.35–0.42; p < 0.00001; I² = 0%). Various other outcomes with statistically significant results are as follows: time to PSA progression (HR = 0.29, 95% CI 0.24–0.35; p < 0.00001, I² = 26%), time to pain progression compared with control therapy (HR = 0.55, 95% CI 0.34–0.89; p = 0.02), and delay in time to subsequent systemic therapy compared with control treatment (HR = 0.39, 95% CI 0.34–0.45; p < 0.00001, I² = 0%). No heterogeneity was observed among included studies (I² = 0%), and there was a prolongation in time to first symptomatic skeletal event (HR = 0.74, 95% CI 0.63–0.87; p = 0.0003, I² = 0%). Funnel plot inspection did not demonstrate asymmetry. The incidence of adverse events and serious adverse events was comparable between the darolutamide therapy and control groups across the included studies. Conclusions: Thus, oral darolutamide therapy was associated with statistically significant improvements in overall survival and multiple disease progression-related outcomes in men with hormone-sensitive prostate cancer. Limited sample sizes and short follow-up necessitate larger studies to confirm its efficacy and safety.