Efficacy and safety of antibody-drug conjugate based therapy in locally advanced or metastatic urothelial carcinoma: a systematic review and network meta-analysis of emerging clinical evidence

Introduction Locally advanced or metastatic urothelial carcinoma (la/mUC) is associated with poor prognosis and limited treatment options. Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach. While previous meta-analyses have shown the efficacy and safety of ADCs in UC, the rapid development of new ADC agents and combination therapies necessitates an updated and comprehensive evidence synthesis. Materials and methods A comprehensive search was performed in PubMed, Embase, Cochrane Library, and Web of Science from inception to September 2025. Interested outcomes include overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AES). RoB 2.0, ROBINS-I tools and GRADE framework were used for quality assessment. Results A total of 30 studies (5 RCTs and 25 single-arm trails), involving 3,631 patients, were included. Network meta-analysis showed that, compared with standard therapy, enfortumab vedotin (EV) in combination with pembrolizumab significantly improved OS (HR = 0.63, 95%CI: 0.43-0.92), ORR (OR = 3.33, 95% CI: 1.65-6.74), and PFS (HR = 0.48, 95% CI: 0.41-0.57). The safety results indicate that the ADC agents have a higher incidence rate of ≥3AES. The analysis of single-arm trails revealed that bulumtatug fuvedotin combined with toripalimab achieved an ORR as high as 88% (95% CI: 73%-96%), while disitamab vedotin-based combination therapy showed the longest median OS. Conclusions This study provides a comprehensive synthesis of the latest clinical evidence on ADC-based monotherapy and combination regimens for la/mUC. The findings confirm the compelling efficacy and manageable safety profile of ADCs in this setting, while also underscoring the need for further clinical trials to validate and refine personalized treatment strategies. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD 420251114022.