Effectiveness and safety of enfortumab vedotin and pembrolizumab in a real-world patient population with urothelial carcinoma: results from a multi-institutional cohort (GUARDIANS)

Abstract Introduction Enfortumab vedotin plus pembrolizumab (EVP) is the standard first-line treatment for metastatic or locally advanced urothelial carcinoma (m/laUC). Real-world patients frequently present with unfavorable clinical characteristics, raising uncertainty about whether outcomes mirror those of the pivotal EV-302/KEYNOTE-A39 trial. This study assessed effectiveness and safety of EVP in a real-world cohort of patients with m/laUC. Materials and methods Retrospective multicenter study including patients treated with EVP across 25 German hospitals (between 03/2022 and 08/2025). Treatment delivery and monitoring followed local clinical standards. Adverse events (AEs) were documented per CTCAE v5.0. Responses were assessed locally using RECIST v1.1. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier methodology. Results A total of 468 patients (median age = 69 years) were included. The overall response rate (ORR) was 50.2% (partial response:37.4%, complete response:12.8%). Median PFS was 10.2 months (95%CI,8.0–12.7). 12-month and 24-month OS rates were 71.9% and 60.6%, respectively. ECOG PS 0–1 and occurrence of skin toxicity were associated with improved outcomes. Any-grade AEs occurred in 81.8% and grade ≥ 3 AEs in 35.8%. Peripheral sensory neuropathy and skin toxicity were the most common AEs. Ten treatment-related fatal events were recorded. Conclusions EVP demonstrated robust effectiveness and manageable toxicity in a large and diverse real-world cohort including patients with divergent histology. Skin toxicity was associated with superior ORR, PFS, and OS. Our findings support EVP as an effective first-line option for patients with m/laUC treated outside clinical trials.