Comparison of first-line treatment strategies for metastatic hormone-sensitive prostate cancer in Japanese clinical practice since 2020: a multicenter registry study

BACKGROUND: Though randomized trials established androgen-receptor signaling inhibitor (ARSI) doublets and darolutamide-docetaxel triplet therapy (TRI) for metastatic hormone-sensitive prostate cancer, combined androgen blockade (CAB) remains widely used in Japan and these strategies have not been compared directly. METHODS: We retrospectively analysed 643 men with M1 disease who began androgen-deprivation therapy during 2020-2026 at 23 Japanese institutions: CAB (113), abiraterone (139), enzalutamide (166), apalutamide (APA; 116), or TRI (109). The primary endpoint was castration-resistance-free survival (PFS1). Groups were compared by Kaplan-Meier analysis and multivariable Cox regression, with inverse-probability-of-treatment weighting, restriction to 2023-2026, and propensity-score matching as sensitivity analyses. RESULTS: Median PFS1 was 16.1, 37.5, 54.9, and 52.9 months, respectively, and was not reached with TRI (P < .001). Adjusted hazard ratios versus CAB were 0.50 (95% CI 0.34-0.72), 0.43 (0.28-0.66), 0.42 (0.26-0.66), and 0.20 (0.10-0.41); triplet versus pooled ARSI doublets was 0.45 (0.24-0.85), exploratory and resting on 12 events. The ordering was preserved in all sensitivity analyses. Prostate-specific antigen 90 (PSA90) rates were similar (94.7%-95.8%), whereas a PSA nadir ≤0.2 ng/ml rose from 43.4% (CAB) to 68.9% (triplet; P < .001). Overall survival was immature (141 deaths). Discontinuation for toxicity was most frequent with APA (19.8%); 54.1% of triplet-treated patients completed six docetaxel cycles. CONCLUSIONS: Intensified first-line treatment was associated with a substantially lower hazard of castration resistance than CAB. The further reduction with TRI rests on few events and is exploratory. Discontinuation for toxicity was most frequent with APA, but ascertainment differed between the registry streams, so safety comparisons are hypothesis-generating.