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

Abstract

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.