Triplet therapy versus androgen receptor pathway inhibitor–doublet therapy in metastatic castration-sensitive prostate cancer: a real-world multicenter retrospective comparison

BACKGROUND: Although pivotal trials have demonstrated the superiority of triplet therapy over androgen deprivation therapy (ADT)-docetaxel doublet therapy, direct comparisons between triplet and androgen receptor pathway inhibitor (ARPI)-ADT doublet therapy remain lacking in real-world practice. This study evaluated the comparative efficacy and safety of triplet versus ARPI-doublet therapy in patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: A total of 837 patients with de novo mCSPC treated between February 2018 and April 2025 were included: 121 received triplet therapy (darolutamide plus docetaxel with ADT), and 716 received ARPI-doublet therapy (abiraterone acetate, enzalutamide, or apalutamide with ADT). The primary endpoint was castration-resistant prostate cancer-free survival (CRPC-FS), and the secondary endpoints were progression-free survival 2 (PFS2) and treatment-related adverse events (TRAEs). Propensity score-based inverse probability of treatment weighting (IPTW) and multiple sensitivity analyses adjusted for baseline imbalances. RESULTS: The median follow-up was 24 months. In the IPTW-adjusted analysis, triplet therapy significantly improved CRPC-FS compared with ARPI-doublet therapy (hazard ratio 0.52, 95% confidence interval 0.39-0.68; P < .001). Subgroup analysis demonstrated consistent benefits in patients with high-volume disease, while no CRPC events occurred in the low-volume subgroup. Sensitivity analyses using propensity score matching and truncated IPTW confirmed the robustness of these findings. Cancer-specific and overall survival were not assessable because of limited follow-up and few events in the triplet cohort. Regarding safety, triplet therapy was associated with higher rates of grade ≥ 3 TRAEs (48.8% vs 8.7%), mainly hematologic toxicities. CONCLUSION: Triplet therapy significantly prolonged CRPC-FS compared with ARPI-doublet therapy in patients with de novo mCSPC, particularly among those with high-volume disease. However, this benefit was accompanied by higher toxicity, underscoring the need to balance efficacy with safety. Longer follow-up is required to determine impacts on PFS2, cancer-specific survival, and overall survival.