The Future of Novel Antibody-drug Conjugates in Localized Urothelial Cancer

Antibody-drug conjugates (ADCs) have recently transformed the paradigm for metastatic urothelial carcinoma treatment. As these therapies demonstrate increasing efficacy and tolerability, attention is turning toward their use in earlier stages of disease. The current molecular targets for ADCs featured in large-scale trials have been Nectin-4 and TROP-2, leading to the development of enfortumab vedotin and sacituzumab govitecan; however, additional promising targets under investigation include HER2, FGFR3, EGFR, and CD-44. While identification of these targets is exciting, the next challenge is harnessing delivery mechanisms to maximize local responses, while limiting systemic toxicity. ADCs have the potential to enhance our ability to offer bladder-sparing therapies to patients with refractory non-muscle-invasive and potentially muscle-invasive disease, who were previously relying on radical cystectomy for treatment. ADCs represent an emerging frontier in the therapeutic landscape of urothelial carcinoma. While their use has thus far been limited to advanced disease, ongoing clinical trials and emerging data suggest possible expanded applications for ADCs in localized bladder cancer. PATIENT SUMMARY: A new standard has emerged for metastatic urothelial carcinoma treatment with the combination of immunotherapy and antibody-drug conjugates. The use of these agents has the potential to transform the space of localized bladder cancer. While promising, many questions remain unanswered about how these new agents will be integrated into the treatment paradigm of non-muscle-invasive and localized muscle-invasive disease.