Episode 10: A Clinical Update on Advanced Urothelial Carcinoma After First-Line Strategies

This Oncology Decoded discussion with Manojkumar Bupathi, MD, MS, executive cochair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI) and medical oncologist with Rocky Mountain Cancer Centers specializing in solid tumors and genitourinary cancers, and Benjamin Garmezy, MD, associate director of genitourinary research and executive cochair of the Genitourinary Cancer Research Executive Committee at SCRI and medical oncologist at SCRI Oncology Partners specializing in genitourinary cancers, provides a comprehensive review of the current therapeutic landscape for metastatic urothelial carcinoma, with a particular focus on patient care after initial treatment failure. The dialogue emphasizes the recent and profound change in approach with the FDA’s approval of the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda). The efficacy of this regimen, which was established in the phase 3 EV-302 trial (NCT04223856), has made it a new frontline standard. The alternative, a combination of gemcitabine and cisplatin with nivolumab (Opdivo) from the phase 3 CheckMate 901 trial (NCT03036098), remains a vital initial option for specific patients who are eligible for cisplatin.

The hosts proceed to explore the intricate considerations for second-line therapy. For individuals who have progressed on the enfortumab vedotin/pembrolizumab combination, potential second-line treatments include platinum-based chemotherapy regimens using gemcitabine/cisplatin or carboplatin. The importance of personalized medicine is underscored, particularly the need for molecular testing to identify FGFR mutations. The FDA-approved FGFR inhibitor, erdafitinib (Balversa), is discussed as a crucial targeted therapy for patients with these specific alterations. Additionally, the podcast highlights the emergent role of HER2-directed therapies and other investigational agents that are currently being developed to address the ongoing need for effective treatments in this setting.

A key topic of the conversation is the practical management of treatment-related toxicities. The clinicians provide valuable perspectives on how to handle adverse effects such as the peripheral neuropathy associated with enfortumab vedotin, as well as the metabolic and dermatologic adverse effects. The podcast also brings to light the lack of clear, evidence-based guidance regarding the optimal duration of therapy and the criteria for discontinuing maintenance treatment, which remains a frequent clinical challenge.

Reference

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed August 13, 2025. https://tinyurl.com/45wkm3bd