Outcomes with androgen-deprivation therapy (ADT) plus androgen receptor pathway inhibitors (ARPIs) in veterans with de novo metastatic castration-sensitive prostate cancer (mCSPC) who were elderly, frail, or had high comorbidity: A subgroup analysis of enzalutamide and high-volume disease.

5094 Background: Clinical trials show significant overall survival (OS) benefits of combining ADT with ARPIs (abiraterone, apalutamide, darolutamide, or enzalutamide [ENZA]) vs ADT in mCSPC. The effects of ADT + ARPI in patients (pts) who are elderly, frail, or have high comorbidity burden remain unclear due to underrepresentation in clinical trials. This observational cohort study examined OS in two subgroups of this population: pts who received ENZA and those with high-volume disease (HVD). Methods: Veterans Health Administration records were used to assess OS in pts with de novo mCSPC treated with ADT + ARPI ± nonsteroidal antiandrogen (NSAA; ADT + ARPI group) or ADT ± NSAA (ADT group). Pts were aged ≥75 years (y) or had Veterans Affairs Frailty Index (VA-FI) > 0.2 or Charlson Comorbidity Index (CCI) ≥3. Subgroups comprised pts who: 1) initiated ADT + ENZA (HVD or low-volume disease); or 2) had HVD with any ARPI. Pts were indexed on first ADT date (Jun 1, 2017–Dec 31, 2022) and followed until censoring (Jun 1, 2025) or death. Mortality risk was estimated using a multivariable, time-varying Cox model to account for time between ADT + ARPI initiation adjusted for volume of disease, age, body mass index, CCI, and prostate-specific antigen level. Results: Of 1,629 pts, 272 (16.7%) received ADT + ENZA and 1,357 (83.3%) received ADT; median follow-up was 34.1 and 23.4 months (mo), respectively. Compared with ADT, the ADT + ENZA subgroup was younger (median age 77.5 vs 81.2 y, standardized mean difference [SMD]: −0.34) with similar frailty (VA-FI > 0.2: 67.3% vs 71.5%, SMD: 0.09) and more HVD (71.7% vs 61.5%, SMD: 0.22). ADT + ENZA was associated with significantly lower risk of death vs ADT (adjusted hazard ratio [aHR] 0.70; 95% CI: 0.60–0.83; P < 0.001; Table). Among 1,541 pts with HVD, 706 (45.8%) received ADT + ARPI and 835 (54.2%) received ADT; median follow-up was 29.1 and 18.8 mo, respectively. Pts who received ADT + ARPI were younger (median age 77.1 vs 81.9 y, SMD: −0.44) and had less frailty (VA-FI > 0.2: 66.2% vs 72.9%, SMD: 0.15). ADT + ARPI was associated with significantly lower risk of death vs ADT (aHR: 0.73; 95% CI: 0.65–0.83; P < 0.001). Conclusions: In this real-world cohort analysis of pts with de novo mCSPC who were elderly, frail, or had high comorbidity, ADT + ENZA was associated with prolonged survival compared with ADT. In pts with HVD, ADT + ARPI was associated with longer survival vs ADT. Subgroup ADTMedian survival,mo (95% CI), n ADT + ARPI a Median survival,mo (95% CI), n aHR (95% CI) b ; P value ENZA 23.4 (21.9–25.2), n = 1,357 36.1 (32.9–40.1), n = 272 0.70 (0.60–0.83); P <0.001 HVD 18.8 (17.5–20.5), n = 835 29.1 (26.0–32.3), n = 706 0.73 (0.65–0.83); P <0.001 a ENZA subgroup treatment arm: ADT + ENZA. b ADT = reference.