Integrating overall survival and quality of life to rank first-line therapies for advanced urothelial carcinoma.

e16588 Background: While survival advantages of first-line therapies for locally advanced or metastatic urothelial carcinoma (la/mUC) are well established, it remains unclear whether treatments with superior overall survival (OS) also provide the most favorable integrated, patient-centered benefit when early health-related quality of life (HRQoL) is considered. We performed a joint evaluation of OS and HRQoL across first-line la/mUC regimens using an integrated network meta-analytic framework. Methods: We performed a network meta-analysis of randomized trials evaluating first-line systemic therapies for la/mUC. OS was synthesized using hazard ratios and ranked using surface under the cumulative ranking curve (SUCRA). HRQoL was assessed using mean change from baseline in EORTC QLQ-C30 Global Health Status (GHS) at approximately 12 weeks, harmonized across trials using the closest available assessment. HRQoL effects were ranked using SUCRA. OS and HRQoL were jointly integrated using the minimum distance criterion (MDC), defined as the minimum distance from the ideal point (OS SUCRA = 1, HRQoL SUCRA = 1), with equal weighting of both outcomes. Analyses focused on enfortumab vedotin plus pembrolizumab, nivolumab plus gemcitabine-cisplatin, and platinum chemotherapy. Results: Enfortumab vedotin plus pembrolizumab ranked highest for OS (OS SUCRA = 0.9997) and demonstrated favorable early HRQoL preservation (GHS SUCRA = 0.97). Nivolumab plus gemcitabine-cisplatin showed intermediate OS benefit (OS SUCRA = 0.64) with substantially lower early HRQoL preservation (GHS SUCRA = 0.20). Platinum chemotherapy ranked lowest for OS (OS SUCRA = 0.02) despite modest early HRQoL preservation (GHS SUCRA = 0.18). When OS and HRQoL were jointly considered, enfortumab vedotin plus pembrolizumab ranked closest to the ideal treatment (MDC = 0.03), followed by nivolumab plus gemcitabine-cisplatin (MDC = 0.88) and platinum chemotherapy (MDC = 1.27). Conclusions: Survival benefit alone does not define optimal first-line therapy in la/mUC. When survival and early quality of life are jointly considered, enfortumab vedotin plus pembrolizumab emerges as the regimen with the most favorable integrated patient-centered benefit, highlighting the importance of incorporating quality-of-life outcomes into comparative treatment evaluation. Integrated ranking of first-line therapies for advanced urothelial carcinoma using the minimum distance criterion (MDC). Treatment OS SUCRA HRQoL SUCRA (GHS) MDC Enfortumab vedotin + pembrolizumab 0.9997 0.97 0.03 Nivolumab + gemcitabine-cisplatin 0.64 0.20 0.88 Platinum chemotherapy 0.02 0.18 1.27 OS SUCRA: Overall survival ranking (higher = better). HRQoL SUCRA: Ranking based on EORTC QLQ-C30 Global Health Status at ~12 weeks (higher = better). MDC: Distance from the ideal point (OS SUCRA = 1; HRQoL SUCRA = 1); lower values indicate better integrated outcomes.