Clinical Impact of Gleason Pattern 5 on Doublet Versus Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer

Why clinicians should know about it

• Picked for Urology (paper of the day, 3 August 2026).

Abstract

BACKGROUND: Upfront treatment intensification with androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor has become a standard approach for metastatic hormone-sensitive prostate cancer (mHSPC). However, prognosis remains poor for some patients despite second-generation androgen receptor antagonist-based doublet therapy. Although triplet therapy with darolutamide and docetaxel is available, its added clinical value over apalutamide- or enzalutamide-based doublet therapy in real-world practice remains unclear. Gleason pattern 5 (GP5) reflects aggressive tumor biology and may be relevant for treatment selection. We evaluated whether triplet therapy was associated with longer castration-resistant prostate cancer-free survival (CRPC-FS) than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC, with a particular focus on effect modification by GP5 status. METHODS: This retrospective multicenter cohort study used the ULTRA-J multicenter collaborative database in Japan. We included systemic treatment-naïve patients with mHSPC who received either doublet therapy with ADT plus apalutamide or enzalutamide, or triplet therapy with ADT, darolutamide, and docetaxel, between February 2018 and October 2024. The final analytic cohort consisted of 294 patients. Overlap weighting was used to reduce treatment-selection bias. The primary endpoint was CRPC-FS, and overall survival (OS) was assessed as a supportive endpoint. Progression-free survival 2 (PFS2) and post-CRPC docetaxel use were evaluated as exploratory post-progression outcomes. RESULTS: The median follow-up duration estimated using the reverse Kaplan-Meier method was 18.0 months in the doublet group and 11.0 months in the triplet group. In the overlap weighting-adjusted overall cohort, triplet therapy was associated with longer CRPC-FS than doublet therapy (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.13-0.64; p = 0.002). A significant interaction was observed for GP5 status (p for interaction = 0.037). In the GP5-positive subgroup, triplet therapy was associated with longer CRPC-FS than doublet therapy (HR, 0.16; 95% CI, 0.06-0.42; p < 0.001), whereas no clear advantage of triplet therapy was observed in the GP5-negative subgroup (HR, 1.85; 95% CI, 0.29-11.94; p = 0.52). No clear difference in OS was observed at the current follow-up. CONCLUSIONS: Triplet therapy was associated with longer CRPC-FS than apalutamide- or enzalutamide-based doublet therapy in systemic treatment-naïve mHSPC. This association appeared more evident in patients with GP5-positive disease. Given the shorter follow-up in the triplet group, limited event numbers in subgroup and PFS2 analyses, and the nonrandomized nature of post-CRPC treatment sequencing, these findings should be interpreted as hypothesis-generating.

Abstract as published, via PubMed.