Concomitant ACE inhibitor or angiotensin receptor blocker use and survival outcomes in de novo metastatic hormone-sensitive prostate cancer receiving ARPI-based therapy: a multicenter propensity-weighted study

Background The renin-angiotensin system (RAS) is expressed in prostate tissue and modulates tumor proliferation, angiogenesis, and androgen receptor signaling. Whether concomitant ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) use affects survival outcomes in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) receiving androgen receptor pathway inhibitor (ARPI)-based therapy remains unknown. Methods This multicenter retrospective study included 211 patients with de novo mHSPC treated with ARPI therapy at three institutions between January 2021 and December 2025. Patients were classified as ACEI/ARB users ( n = 87) or non-users ( n = 124). The primary endpoint was progression-free survival (PFS); overall survival (OS) and PSA response rates were secondary endpoints. Multivariable Cox regression and stabilized inverse probability of treatment weighting (IPTW) were used for survival analyses, with propensity-score matching and a statin-adjusted model as sensitivity analyses. Exploratory subgroup analyses were corrected for multiple comparisons using the Benjamini–Hochberg false discovery rate procedure. Results At a median follow-up of 20.9 months, progression occurred in 19.5% of ACEI/ARB users versus 50.8% of non-users, and death in 4.6% versus 20.2%. In multivariable analysis, ACEI/ARB use was associated with improved PFS (HR 0.35, 95% CI 0.20–0.65, p = 0.001) and OS (HR 0.28, 95% CI 0.09–0.88, p = 0.029; 29 deaths, 4 among ACEI/ARB users). The PFS association persisted after IPTW adjustment (HR 0.57, p = 0.032) and across propensity-score matching, statin-adjusted, and hypertensive-only sensitivity analyses. OS estimates were directionally consistent but imprecise because of the small number of deaths (IPTW HR 0.24, 95% CI 0.06–0.91). PSA50 and PSA90 response rates were significantly higher in ACEI/ARB users (95.4% vs. 82.3%, p = 0.004; 87.4% vs. 71.0%, p = 0.005). Conclusions In this retrospective cohort, concomitant ACEI/ARB use was associated with improved PFS and deeper PSA responses in patients with de novo mHSPC receiving ARPI therapy. The OS findings were consistent in direction but underpowered because of the small number of deaths. Given the potential for residual and unmeasured confounding, these findings should be considered hypothesis-generating and require external validation and prospective evaluation.