In this episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS, and Benjamin Garmezy, MD, discussed treatment for urothelial carcinoma following updates from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. With enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) now the frontline standard, the hosts focused on emerging biomarker-driven strategies that show efficacy after progression on first-line care.

Bupathi outlined the current algorithm, with platinum-based chemotherapy—typically gemcitabine plus carboplatin—representing the most common second-line option. Beyond chemotherapy, sacituzumab govitecan-hziy (Trodelvy) retained its NCCN category 2 recommendation despite losing its FDA accelerated approval in urothelial carcinoma after the confirmatory phase 3 TROPiCS-04 trial (NCT04527991) did not yield an overall survival benefit. For biomarker-selected patients, erdafitinib (Balversa) is available for FGFR3-altered disease, and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is FDA-approved for HER2 immunohistochemistry (IHC) 3+ solid tumors, including bladder cancer.

Garmezy, an investigator on the phase 1 NEXUS-01 trial (NCT06465069), discussed data on LY4052031, a nectin-4-directed antibody drug conjugate (ADC) carrying a topoisomerase payload, in patients previously treated with enfortumab vedotin, which also targets nectin-4 but delivers a different payload class. The trial showed response rates of 30% to 40% in that population, with some durable responses, suggesting resistance to enfortumab vedotin often reflects payload-specific resistance rather than loss of nectin-4 expression. Garmezy described the data as hypothesis-generating.

Regarding patients who progress on frontline enfortumab vedotin plus pembrolizumab, the hosts said they would prioritize a biomarker-directed option, such as erdafitinib for FGFR3 alterations or T-DXd for HER2 expression, when a trial is not available, while reserving chemotherapy for later lines. Given the lack of comparative data to help guide a choice between erdafitinib and T-DXd when a patient has both an FGFR3 alteration and HER2 expression, the hosts noted that selections come down to shared decision-making around toxicity profile and route of administration.

Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is the president and a medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.