Patterns of local therapy following enfortumab vedotin in advanced urothelial carcinoma

• Only 24% of EV-treated patients received any bladder-directed local therapy. • Cystectomy after EV showed the longest survival, exceeding 600 days in some. • Local therapies were performed early, mostly within 4 to 6 months of EV initiation. • Most radiation and cystectomy occurred in first-line treatment after EV. • Early multidisciplinary evaluation may identify patients for consolidative therapy. Enfortumab vedotin (EV) + pembrolizumab (P) is now first-line standard-of-care for locally advanced or metastatic urothelial carcinoma (la/mUC) after the phase 3 EV-302 trial doubled overall survival (OS) vs. platinum chemotherapy. Whether definitive local therapy—radiation, transurethral resection of bladder tumor (TURBT) or radical cystectomy adds benefit after EV remains unclear. We performed a multi-institutional, retrospective cohort study using the TriNetX analytics network. Adults with ICD-10-CM C67.0–C67.9 or equivalent SNOMED CT codes for bladder cancer who received ≥1 dose of EV (identified by HCPCS J9177) between January 2019 and 2 February 2025 were included. Primary endpoints were (1) utilization of any bladder-directed therapy after EV, (2) time from EV initiation to local therapy, and (3) OS, all stratified by treatment modality. Kaplan–Meier estimates and log-rank tests were used. Among 459 EV-treated patients (mean age 73.1 ± 10 years; 68.9% male), median follow-up was 251 days (IQR 356). Only 108 (23.5%) underwent local therapy: external-beam radiotherapy (EBRT) 71.3%, cystectomy 14.8%, TURBT 13.9%. Local interventions clustered early with median 119 days for TURBT, 134 days for cystectomy, 164 days for EBRT and occurred almost exclusively in line-of-therapy (LOT) 1 (>90% of EBRT, 100% of cystectomies). Median OS for the cohort was 217 days. Survival varied by modality: cystectomy, median not reached (>600 days in several patients); TURBT 316 days; EBRT 217 days; no local therapy 204 days. Cystectomy retained a favorable survival signal in adjusted analysis. In real-world practice, three-quarters of la/mUC patients treated with EV receive no subsequent bladder-directed therapy. When employed early, radical cystectomy was associated with the longest survival, supporting multidisciplinary evaluation of surgical consolidation in select EV responders. Prospective trials are warranted to define patient selection, timing, and comparative efficacy of surgery vs. radiotherapy in the EV era.