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

## TL;DR

This paper reviews why some bladder cancer patients respond to antibody-drug conjugates while others do not, and how to overcome resistance.

## Contribution

The paper provides a comprehensive overview of response predictors and resistance mechanisms specific to ADCs in urothelial carcinoma.

## Key findings

- ADCs like enfortumab vedotin and sacituzumab govitecan show clinical benefits in urothelial carcinoma.
- Resistance to ADCs is influenced by factors like antigen expression, genomic changes, and the tumor environment.
- Emerging biomarkers and combination therapies may improve ADC effectiveness and durability.

## Abstract

Urothelial carcinoma, a common type of bladder cancer, has been difficult to treat once it spreads beyond the bladder. Antibody–drug conjugates are a newer form of cancer therapy that combine targeted antibodies with powerful cancer-killing drugs, allowing treatment to be delivered more directly to tumor cells. Several of these treatments have shown meaningful benefits for patients and are now used in both advanced and earlier stages of disease. However, not all patients respond well, and many cancers eventually stop responding to therapy. This review explains what is currently known about why these treatments work for some patients but not others, including differences in tumor biology, genetic changes, and the tumor environment. It also discusses new markers that may help predict response and future strategies to overcome resistance. These insights may guide future research and improve how treatments are selected and combined in clinical practice.

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.