Real-world outcomes of enfortumab vedotin plus pembrolizumab compared with platinum-based chemotherapy in metastatic urothelial carcinoma in a propensity-matched global analysis.

e16597 Background: Enfortumab vedotin plus pembrolizumab has shown superior efficacy compared with platinum-based chemotherapy in randomized trials for untreated locally advanced or metastatic urothelial carcinoma. However, comparative real-world evidence evaluating survival and healthcare utilization with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy remains limited. This study examines real-world outcomes associated with these treatment strategies in routine clinical practice. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adult patients ( > 18 years) with metastatic urothelial carcinoma initiating first-line enfortumab vedotin plus pembrolizumab or platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) between January 2020 and December 2024 were identified. One-to-one propensity score matching (PSM) was performed to balance baseline demographics and key clinical comorbidities, including chronic kidney disease, diabetes, neuropathy, and smoking history. The primary outcome was overall survival (OS). Secondary outcomes included inpatient hospitalization and palliative care encounters. Kaplan–Meier analyses, log-rank testing, and hazard ratios (HRs) were calculated. Risk differences and risk ratios were estimated for secondary outcomes. All outcomes were assessed in the matched cohorts. Results: Among 2,264 eligible patients, 851 received enfortumab vedotin plus pembrolizumab and 1,413 received platinum-based chemotherapy. After PSM, 771 patients were included in each group with well-balanced baseline characteristics. Median OS was significantly longer in the enfortumab vedotin plus pembrolizumab group compared with platinum chemotherapy (679 vs 467 days), corresponding to a 20% reduction in mortality risk (HR 0.80; 95% CI 0.70–0.92; p = 0.002). Patients treated with enfortumab vedotin plus pembrolizumab also experienced fewer inpatient hospitalizations (62.5% vs 71.9%) and fewer palliative care encounters (39.9% vs 46.3%) compared with those receiving platinum-based chemotherapy. Median follow-up duration was similar between groups (392 vs 453 days). Conclusions: In this large real-world propensity-matched analysis, first-line enfortumab vedotin plus pembrolizumab was associated with improved overall survival and lower healthcare utilization compared with platinum-based chemotherapy in metastatic urothelial carcinoma. These findings support the effectiveness of enfortumab vedotin plus pembrolizumab in routine clinical practice and provide complementary evidence to randomized trials, particularly for patients who may be underrepresented in clinical trial populations.