Prognostic Stratification in High-Volume Metastatic Hormone-Sensitive Prostate Cancer Treated With First-Line Androgen Receptor Pathway Inhibitor-Based Combination Therapy.

OBJECTIVES: We aimed to stratify clinical risk among patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) treated with first-line androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT). METHODS: We retrospectively analyzed 626 patients with high-volume mHSPC treated with ARPI+ADT between November 2016 and April 2025. A multivariable Cox model for time to castration-resistant prostate cancer (TTCRPC) was developed using nine baseline characteristics, including age, hemoglobin, ECOG performance status, clinical T stage, ISUP grade group, EOD score, lung and liver metastases, and LDH, selected based on clinical relevance and prior evidence. Model discrimination and calibration were assessed using bootstrap internal validation. Patients were stratified into three risk groups based on the linear predictor, and associations with TTCRPC and overall survival (OS) were evaluated. RESULTS: The median follow-up was 34.8 months. Clinical T4 stage, ISUP grade group 5, and higher LDH were independently associated with shorter TTCRPC, whereas lung metastasis was associated with longer TTCRPC. The model had an optimism-corrected C-index of 0.69. TTCRPC differed significantly across the low-, intermediate-, and high-risk groups (p < 0.001); compared with the low-risk group, the HRs were 1.48 (95% CI 1.00-2.17) for the intermediate-risk group and 4.09 (95% CI 2.90-5.77) for the high-risk group. OS also differed significantly across the three risk groups (p < 0.001). CONCLUSIONS: In patients with high-volume mHSPC treated with ARPI+ADT, the model showed modest discrimination for TTCRPC and identified groups with different TTCRPC and OS outcomes. These findings suggest the presence of clinically heterogeneous subgroups within high-volume mHSPC and warrant independent validation in external cohorts.