Concurrent use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) in patients (pts) with advanced urothelial carcinoma (UC) receiving enfortumab vedotin (EV) plus pembrolizumab (P) therapy.

759 Background: Some advanced UC pts treated with EV plus P therapy have primary refractory disease or develop progressive loss of response to therapy, highlighting the need for synergistic approaches to augment treatment efficacy and duration of response. UCs that express higher levels of transforming growth factor-β (TGF-β) demonstrate poor responses to immunotherapy, while blockade of the renin-angiotensin system inhibits TGF-β. As such, we examined whether concurrent use of an ACEi or ARB during EV plus P therapy would correlate with improved clinical outcomes in pts with advanced UC. Methods: This is a retrospective analysis of advanced UC pts, who initiated EV plus P therapy at 6 academic institutions from 8/1/2018 to 9/1/2025. Pts needed to have at l east 1 whole body scan to assess for treatment response, which was interpreted using RECIST by the treating physician. Patients were divided into 3 subgroups: ACEi positive (cohort 1), ARB positive (cohort 2), or ACEi/ARB negative (cohort 3) at EV plus P start. Extracted data included demographic, clinical, treatment, and genomic variables. Primary study endpoint was median progression free survival (mPFS), defined as time from EV plus P initiation to progressive disease by RECIST version 1.1 criteria. Data was analyzed using descriptive statistics and Kaplan-Meier estimation. Results: A total of 253 pts were included, 73% were male, and median age was 72 years [range, 27 to 95]. Cohorts 1, 2, and 3 comprised 39, 58, and 156 pts respectively. Median pt age across the cohorts was similar, but the distribution of ages was skewed younger in cohort 3 (median 72, range 27-92) compared to cohorts 1 (72, 57-95) and 2 (75, 57-95) (Kruskal-Wallis, p = 0.011). Cohort 2 pts demonstrated a lower median glomerular filtration rate (GFR) (49, 10-97) compared to either cohort 1 (59, 16-96) or 3 (61, 10-122) (p = 0.055). There were otherwise no significant differences in characteristics among the cohorts. At a median follow-up of 11.1 months (mos), mPFS was 16, 18, and 12 mos in cohorts 1, 2 and 3, respectively (p = 0.6). Median overall survival (mOS) was 24, 21 and 33 mos in cohorts 1, 2, and 3, respectively (p = 0.7). Objective response rate (ORR) was 59%, 57%, and 57% in cohorts 1, 2, and 3, respectively. On multivariate analysis, age at EV plus P initiation, GFR, and ECOG variables correlated with inferior mPFS. Conclusions: Concurrent use of ACEi or ARB during EV plus P therapy did not affect outcomes in pts with advanced UC in this limited retrospective dataset. Analysis of tumor TGF-β expression and correlation with ACEi/ARB use could better elucidate the effect of these agents on responses to therapy in advanced UC. Prospective analysis could elucidate the effect of possible confounding factors such as ACEi/ARB dose and duration.