Enfortumab Vedotin−Induced Cutaneous Toxic Effects and Survival in Urothelial Carcinoma

Importance: Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancer. Cutaneous adverse events (cAEs) are common during EV therapy, with prior studies suggesting an association between EV-related cAEs and improved survival; however, there are insufficient data to delineate the survival benefit of EV-induced cAEs from those associated with concurrent immune checkpoint inhibitors (ICIs). Objective: To evaluate the association of EV-induced cAEs with survival and to characterize the timing and morphologic mechanisms of EV-induced cAEs. Design, Setting, and Participants: This was a multi-institutional retrospective study of patients with locally advanced or metastatic urothelial cancer treated with EV between 2020 and 2025. Patient characteristics were extracted manually, and likelihood scoring was used to attribute cAEs to either EV or other causes. Data were analyzed from September 2025 to January 2026. Exposure: EV treatment. Main Outcomes and Measures: Progression-free (PFS) and overall (OS) survival were estimated using the Kaplan-Meier method. Multivariable time-varying and landmark Cox regression models were used to evaluate associations between EV-induced cAE and survival. Sensitivity analyses were performed at landmarks from 15 to 105 days. Results: Of 449 patients (mean [SD] age, 71.9 [9.2] years; 122 females [27.2%] and 327 males [72.8%]), 206 (45.9%) developed a cAE; 39 (18.9%) were high-grade and 127 (61.7%) were attributed to EV. The most common cAEs were pruritus (85 patients [41.3%]), unspecified and desquamating dermatitis (76 [37.3%]), and morbilliform dermatitis (58 [27.7%]). Across all treatment groups, survival was longer in patients with EV-induced cAEs. Developing an EV-induced cAE was protective across all landmark times assessed, with a hazard ratio of 0.60 (95% CI, 0.43-0.82; P < .001) for PFS and 0.46 (95% CI, 0.31-0.67; P < .001) for OS at 30 days (primary landmark). Early-onset EV-induced cAEs were protective at all landmark times and high-grade EV-induced cAEs were not associated with worse survival outcomes. Conclusions and Relevance: In this cohort study, EV-induced cAEs were independently associated with improved PFS and OS in patients with locally advanced or metastatic urothelial cancer, even after accounting for immortal time bias and ICI exposure. Distinguishing EV-induced cAEs from other causes in timeline and morphologic mechanisms may help guide oncologic and dermatologic treatment and management.