Dr Gupta on Future Directions With Enfortumab Vedotin/Pembrolizumab in Urothelial Carcinoma

“We want to take a deep dive into patients who had responses and [see] what their dose modifications were. [We want to determine] if patients can still achieve the overall survival benefit [with enfortumab vedotin plus pembrolizumab vs chemotherapy] with a reduced number of [treatment cycles].”

Shilpa Gupta, MD, the director of Genitourinary Medical Oncology at the Taussig Cancer Institute and the coleader of the Genitourinary Oncology Program in the Department of Hematology and Medical Oncology at the Cleveland Clinic, discussed future research directions for enfortumab vedotin-efjv (Padcev) in combination with pembrolizumab (Keytruda) for the treatment of urothelial carcinoma.

During the 2025 Genitourinary Cancers Symposium, investigators presented findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) which showed that treatment-naive patients with locally advanced or metastatic urothelial carcinoma who received enfortumab vedotin plus pembrolizumab experienced a significant overall survival (OS) benefit compared with those who received chemotherapy (HR, 0.51; 95% CI, 0.43-0.61; nominal 2-sided P = .00001). The combination also produced a significant benefit in terms of progression-free survival vs chemotherapy (HR, 0.48; 95% CI, 0.41-0.57; nominal 2-sided P < .00001).

The OS benefit with enfortumab vedotin plus pembrolizumab vs chemotherapy was maintained across key prespecified patient subgroups. The most pronounced benefit was observed among those with an ECOG performance status of 0 (HR, 0.394; 95% CI, 0.296-0.524).

The safety profile reported in the combination arm was consistent with prior data with no new safety signals, cementing the regimen’s place as the standard of care in this patient population, according to Gupta and study authors.

In the future, investigators want to further assess patients who achieved responses and evaluate their dose modifications, Gupta explained. Prior findings have suggested that the OS benefit with enfortumab vedotin plus pembrolizumab can be maintained with a lower number of cycles of therapy, she concluded.