Real-world overall survival improvements in metastatic urothelial carcinoma across three key therapeutic temporal periods

BACKGROUND: Over the past decades, treatment of metastatic urothelial carcinoma (mUC) has been transformed by three backbone therapies: platinum-based chemotherapy (PBC), immune checkpoint inhibitors (ICIs), and antibody-drug conjugates (ADCs), used alone or in combination. Evaluating temporal trends in overall survival (OS) is essential to contextualize therapeutic progress and identify unmet needs. PATIENTS AND METHODS: Using the TriNetX research database, we conducted a retrospective, large-scale outcome analysis of patients with mUC who received at least one line of therapy across international health care institutions. Patients were stratified into three therapeutic temporal periods (TPs): PBC TP (1999-2015), ICI TP (2016-2018), and ADC TP (2019-2025). Baseline characteristics were compared using standard statistical methods. OS was estimated using Kaplan-Meier analysis. Propensity score matching (PSM) adjusted for age, sex, stage, comorbidities, and treatment lines. RESULTS: Among 4720 patients with mUC, 2383 who received first-line therapy between 1999 and 2025 were included (783 PBC TP, 663 ICI TP, and 937 ADC TP). Median age was ∼70 years across periods, and baseline characteristics were balanced (all P > 0.05). Across TPs, 51.7%, 32%, and 20% of patients received PBC, ICIs, and ADCs, respectively. Receipt of second- and third-line therapy remained stable (∼52% and ∼26%, respectively). Median OS increased from 13.5 months in the PBC TP to 17.5 months in the ICI TP and 21.1 months in the ADC TP (ADC versus PBC P = 0.0017). After PSM, median OS was 13.4, 17.3, and 22.3 months in the PBC, ICI, and ADC TPs, respectively (ADC versus PBC P = 0.005). Among patients receiving chemotherapy only in their respective PBC, ICI, and ADC TPs, OS was 13.5, 14.6, and 17.1 months (PBC versus ADC P = 0.06). CONCLUSIONS: OS in mUC has improved substantially over time, with the greatest gains observed in the ADC TP. Improvements were evident even among patients not receiving TP-specific agents, suggesting that broader advances in diagnostics, supportive care, and health care delivery contributed to real-world survival gains.