What Role Will The EV-304 Regimen Occupy in The Bladder Cancer Paradigm?

In the latest episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS; and Benjamin Garmezy, MD, spoke about the clinical utility of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for those with muscle-invasive bladder cancer (MIBC) and similar patient populations. They highlighted the “transformational” potential of this therapeutic regimen in the context of findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) that investigators presented at the 2026 ASCO Genitourinary Cancers Symposium.

Although certain data from the EV-304 trial, including the improvements in pathologic complete responses (pCRs) with the enfortumab vedotin combination over gemcitabine/cisplatin, represent “historical gamechangers”, the hosts pointed towards some uncertainty related to outcomes for those with varying or mixed histologies. According to Bupathi, it may still make sense to administer chemotherapy with immunotherapy in some of these subgroups.

The hosts also considered how many cycles of enfortumab vedotin plus pembrolizumab should be administered across the neoadjuvant and adjuvant settings, noting how markers like circulating tumor DNA may help inform treatment schedules. Additionally, they highlighted a need for additional research to clarify whether cystectomy could be spared for patients receiving this combination regimen while translating the benefits observed in trials like EV-304 to the real world.

The discussion also touched upon the treatment of those with metastatic disease, as the hosts considered how dosing cycles, consolidated radiotherapy, and cystectomy with nodal dissection fit into the treatment algorithm for these patients. Garmezy and Bupathi also discussed how the efficacy and safety of the enfortumab vedotin combination compared with gemcitabine plus nivolumab (Opdivo), noting how the EV-304 regimen may be simpler to administer and manage.

Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is president of 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.

Reference

Galsky MD, Valderrama BP, Maruzzo M, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. 2026;44(suppl 7):LBA630. doi: 10.1200/JCO.2026.44.7_suppl.LBA630