First-Line Enfortumab Vedotin Plus Pembrolizumab vs Gemcitabine Plus Cisplatin for Metastatic Urothelial Carcinoma

Importance: Enfortumab vedotin plus pembrolizumab (EV/P) recently emerged as the preferred first-line treatment regimen for metastatic urothelial carcinoma (mUC), but evidence outside trial settings is relatively limited. Objective: To evaluate outcomes associated with first-line EV/P compared with gemcitabine plus cisplatin (G/C) in patients with mUC. Design, Setting, and Participants: This retrospective cohort study used the TriNetX database. Adults with mUC initiating first-line EV/P or G/C between September 2007 and September 2025 were included. Cohorts were propensity score matched for comparison by demographic characteristics, comorbidities, kidney function, and location of metastatic disease. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included time to next treatment (TTNT), time to hospitalization within 90 days of treatment initiation (EHA), and adverse events (AEs). Outcomes were compared using Kaplan-Meier analysis and log rank test, reporting hazard ratios (HRs) and 95% CIs. Results: The study included 4433 patients (1841 receiving EV/P and 2592 receiving G/C), with the EV/P group being significantly older (mean [SD] age, 70.6 [10.1] years vs 67.2 [10.6] years; P < .001) and having a higher proportion of Black patients (129 [6.7%] vs 139 [5.3%]; P = .04) and White patients (1445 [76.0%] vs 1614 [61.8%]) but a smaller proportion of Asian patients (145 [7.6%] vs 326 [12.5%]; P < .001). The EV/P group also carried a greater comorbidity burden, including higher rates of heart failure, diabetes, and obesity, while baseline characteristics were well balanced after propensity score matching. First line EV/P was associated with lower risk of death (HR, 0.70; 95% CI, 0.63-0.79), longer median OS (20 vs 11 months), lower risk of EHA (HR, 0.73; 95% CI, 0.64-0.83), and longer TTNT (median, 35 vs 10 months; HR, 0.49; 95% CI, 0.39-0.61). Receipt of EV/P at first line was associated with higher rates of rash, hyperglycemia, and hypothyroidism but fewer cytopenias and gastrointestinal toxic effects. Conclusions and Relevance: In this retrospective cohort study of patients with mUC, EV/P was associated with longer OS, delayed TTNT, and lower time to EHA compared with G/C. These findings support the broader adoption of EV/P as first-line therapy in routine clinical practice.