For decades, treatment options for locally advanced and metastatic urothelial carcinoma remained largely unchanged, with platinum-based chemotherapy serving as the only effective systemic therapy. The advent of immune checkpoint inhibitors (ICIs) represented the first major advance in the postplatinum setting; however, these agents benefit only approximately 20% of patients. Consequently, effective treatment options remained limited for patients progressing after platinum chemotherapy and ICIs until the emergence of antibody drug conjugates (ADCs), which have reshaped the therapeutic landscape in urothelial cancer. ADCs such as enfortumab vedotin, targeting Nectin-4 in combination with pembrolizumab, have not only displaced platinum-based chemotherapy as the decades-long standard of care in locally advanced and metastatic disease but also moved into the perioperative setting for muscle-invasive bladder cancer. ADCs targeting human epidermal growth factor receptor 2 and trophoblast cell surface antigen 2 have also demonstrated clinical activity, and ongoing trials are evaluating next-generation ADCs designed to improve efficacy while limiting off-target toxicities through optimized targets, payloads, and linker technologies. In this review, we summarize the ADCs shaping the field of urothelial carcinoma, emerging agents, and combination strategies across disease settings. We also review clinically relevant toxicities, mechanisms of resistance, and mitigation strategies. Future efforts should focus on dose optimization, biomarker-driven patient selection, and treatment de-escalation to maintain efficacy while limiting toxicity for patients with urothelial carcinoma.
JCO oncology practice. 2026 Jul 27 [Epub ahead of print]
Samer Salem, Kainat Warraich, Shilpa Gupta
Department of Internal Medicine, Cleveland Clinic, Cleveland, OH., Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.