Treatment-free survival (TFS) in patients with advanced urothelial carcinoma (aUC) treated with enfortumab vedotin (EV)–based therapy.

4576 Background: EV as monotherapy or with pembrolizumab (EVP) has shown robust efficacy in patients with aUC. Despite lack of data, treatment breaks (TB) with EV are frequently utilized due to toxicity or patient/physician preference. In this retrospective real-world analysis, we evaluated TFS after temporary or permanent EV discontinuation in patients with aUC. Methods: A multicenter cohort of patients with aUC treated with EV/EVP between 01/2015 through 12/2025 were included. Patients were categorized in groups with or without TB (defined as ≥6 weeks between EV doses without progression). Baseline characteristics were summarized using descriptive statistics, and comparison was performed using the chi-square test/Fisher's exact and t-test, as appropriate. TFS was estimated using the Kaplan–Meier method among TB+ patients. Overall survival (OS) and progression-free survival (PFS) were estimated for both cohorts using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable models adjusted for baseline variables evaluated factors associated with TFS, OS and PFS. Results: From a total of 172 patients eligible for inclusion, 25 (14%) received TB and 148 (86%) did not. Median age was 72.5 years. Most patients were White (76.3%), had primary bladder cancer (89%), and received EVP (63%). Overall, 30% had ≥1 prior line of therapy. Baseline characteristics did not differ significantly between patients with and without TB. Most common reason for TB was treatment toxicity (52%) and a minority (20%) continued pembrolizumab during their break. The median TFS was 3.6 months (95% CI 3.0, 8.3), with 28% experiencing a TFS ≥24 weeks. TB did not compromise outcomes, and patients with a TB demonstrated longer median PFS (13.5 vs. 7.7 months, p=0.05) and OS (not reached vs 21.8 months, p=0.008). Prior radiation therapy (OR 0.18 (95% CI 0.06-0.53, p=0.002) and prior adjuvant chemoimmunotherapy (OR 0.18 (95% CI 0.04-0.77, p=0.02) were independently associated with decreased odds of experiencing a TB. Conclusions: Treatment break on EV therapy did not compromise outcomes and resulted in TFS lasting ≥6 months in a subset of patients. Rational treatment de-escalation strategies in selected patients need to be prospectively investigated to mitigate long-term toxicity in patients with aUC undergoing EV-based therapy.