An update on antibody-drug conjugates in urothelial carcinoma: state of the art strategies and what comes next

Abstract

In recent years, considerable progress has been made in increasing the knowledge of tumour biology and drug resistance mechanisms in urothelial cancer. Therapeutic strategies have significantly advanced with the introduction of novel approaches such as immune checkpoint inhibitors and Fibroblast Growth Factor Receptor inhibitors. However, despite these novel agents, advanced urothelial cancer is often still progressive in spite of treatment and correlates with a poor prognosis. The introduction of antibody-drug conjugates consisting of a target-specific monoclonal antibody covalently linked to a payload (cytotoxic agent) is a novel and promising therapeutic strategy. In December 2019, the US Food and Drug Administration (FDA) granted accelerated approval to the nectin-4-targeting antibody-drug conjugate, enfortumab vedotin, for the treatment of advanced or metastatic urothelial carcinomas that are refractory to both immune checkpoint inhibitors and platinum-based treatment. Heavily pre-treated urothelial cancer patients reported a significant, 40% response to enfortumab vedotin while other antibody-drug conjugates are currently still under investigation in several clinical trials. We have comprehensively reviewed the available treatment strategies for advanced urothelial carcinoma and outlined the mechanism of action of antibody-drug conjugate agents, their clinical applications, resistance mechanisms and future strategies for urothelial cancer.

Keywords: Antibody–drug conjugate; Bladder; Enfortumab vedotin; HER2; Immunotherapy; Nectin-4; Sacituzumab govitecan; Urothelial cancer.

Fig. 1

Different types of ADCs tested in urothelial cancer. DXD deruxtecan, DM-1 emtansine, MMAE monomethyl auristatin E, HER2 human epidermal growth factor receptor 2, T-DM1 trastuzumab emtansine, TROP-2 Trophoblast cell surface antigen 2, SLITRK Slit- and Trk-like protein