Unmet Potential of Antibody-Drug Conjugates: An Evaluation of the Past, Present, and Future of Antibody-Drug Conjugate Development in Advanced Urothelial Carcinoma.

Antibody-drug conjugates (ADCs) represent an emerging class of therapeutics across solid tumor oncology and are already positioned as a cornerstone therapy for patients with urothelial carcinoma (UC). In recent years, there has been a paradigm shift in the therapeutic landscape as frontline treatment of UC formerly relied on the use of platinum-based agents and has now evolved to include combination strategies with ADCs. These dramatic changes are due in part to our improved understanding of the molecular features of bladder tumors and the identification of tumor-associated antigens specific to UC, which may serve as druggable targets. Despite notable advances and the clinical success of ADCs in other malignancies, their full potential in UC remains largely unmet. Early clinical success of enfortumab vedotin and sacituzumab govitecan demonstrated antitumor activity; however, there are multiple challenges with these ADCs, including on-target, off-tumor toxicity and difficulty in maintaining sustained responses. Newer-generation ADC constructs, either alone or as part of combination approaches, are currently under investigation. This review examines the historical development, current landscape, and emerging trends in ADC therapy for UC, highlighting both the progress made and obstacles that continue to hinder optimal therapeutic outcomes.