Predictors of Response and Mechanisms of Resistance to Antibody Drug Conjugates in Urothelial Carcinoma

Antibody–drug conjugates (ADCs) have reshaped the treatment landscape of urothelial carcinoma (UC) by enabling selective delivery of highly potent cytotoxic agents to tumor cells. Enfortumab vedotin, sacituzumab govitecan, and HER2-directed ADCs have demonstrated meaningful clinical activity across metastatic and earlier disease settings, with enfortumab vedotin plus pembrolizumab now established as a first-line standard of care. Despite these advances, therapeutic responses remain heterogeneous, and resistance frequently limits durability. This review summarizes current knowledge on predictors of response and mechanisms of resistance to ADCs in UC, highlighting the roles of target antigen expression and heterogeneity, genomic alterations, payload sensitivity, drug efflux transporters, and tumor microenvironmental factors. We discuss emerging biomarkers beyond antigen abundance, patterns of cross-resistance and treatment sequencing, and evolving strategies to overcome resistance, including next-generation ADC design and rational combination therapies. Advancing biomarker-driven patient selection and addressing mechanisms of resistance will be critical to maximizing the durability and clinical impact of ADCs in urothelial carcinoma.