Primary GP5 Independently Linked to Worse Survival but Not CRPC Progression in Low-Volume mHSPC

Although androgen receptor pathway inhibitor (ARPI)-based doublet therapy represents a standard treatment approach for low-volume metastatic hormone-sensitive prostate cancer (mHSPC), clinical responses and outcomes remain heterogeneous. To evaluate prognostic determinants in this setting, an international multicenter collaborative study retrospectively analyzed 289 patients with low-volume de novo mHSPC who received upfront ARPI-based doublet therapy between 2018 and 2026. The primary endpoint evaluated was progression to castration-resistant prostate cancer (CRPC), with cancer-specific survival (CSS) and overall survival (OS) analyzed as secondary endpoints. An exploratory analysis also compared the achievement of prostate-specific antigen (PSA) levels ≤ 0.2 ng/mL between doublet and triplet regimens.

Over a median follow-up of 24.6 months, 61 patients developed CRPC, 15 patients died from prostate cancer, and 26 patients died from any cause. Primary Gleason pattern 5 (GP5) was associated with CRPC progression on univariable analysis, but this relationship did not persist in multivariable analysis. However, primary GP5 was independently associated with inferior survival outcomes, including worse CSS (hazard ratio [HR] 9.09, 95% confidence interval [CI] 2.85–34.87; P = 0.0002) and OS (HR 2.97, 95% CI 1.21–7.22; P = 0.0184), though these secondary findings were derived from a limited number of events.

In exploratory assessments, triplet therapy was associated with increased odds of achieving a PSA ≤ 0.2 ng/mL among patients with primary GP5-positive disease; nevertheless, the interaction between treatment type and primary GP5 status was not significant (P for interaction = 0.4095). The authors concluded that primary GP5 is associated with unfavorable oncological outcomes in low-volume de novo mHSPC managed with upfront ARPI-based doublets, noting that its prognostic significance and potential utility for guiding treatment intensification require further validation.