Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

Simple Summary For metastatic urothelial cancer (UC), platinum-based chemotherapy and immunotherapy are used, with newer treatments like monoclonal antibodies (e.g., pembrolizumab) showing varied success. Traditional treatments often fail to provide long-term responses. Advances in molecular understanding of UC have led to targeted therapies, identifying six UC subclasses influencing treatment responses. Promising drugs include the fibroblast growth factor receptor inhibitor erdafitinib and antibody-drug conjugates (ADCs). ADCs represent a significant advancement in UC treatment, using monoclonal antibodies linked to cytotoxic agents to target cancer cells. UC is suitable for ADC therapy due to high antigen expression, enhancing efficacy while reducing systemic toxicity. Despite immune checkpoint inhibitors, advanced UC progresses rapidly with poor survival rates. Notable ADCs include enfortumab vedotin, effective alone and with pembrolizumab, and sacituzumab govitecan, showing effectiveness in studies. This review covers ADC mechanisms, mono- and combination therapies, resistance, and future perspectives, highlighting ADCs' vital role in treating UC.Abstract Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease.