Updated EV-302 analysis continues to support EV/P for locally advanced/metastatic urothelial carcinoma

The phase 3 EV-302 trial (NCT04223856) demonstrated that enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) significantly improved progression-free survival and overall survival (OS) vs platinum-based chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). These findings led to FDA approval of the regimen for this indication in December 2023.

At the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois, 3½-year follow-up data from the trial were presented, continuing to show superior efficacy with the combination regimen vs chemotherapy.¹ At a median follow-up of 42.8 months, the median OS was 33.6 months in the EV/P arm vs 15.9 months in the chemotherapy arm. The 42-month OS rate was 44% with the combination vs 24.6% with chemotherapy (HR, 0.53; 95% CI, 0.45 to 0.63).

The complete response (CR) rate was 45.1% vs 32.8%, respectively. Among those in the combination arm who achieved a CR, 66.2% initially achieved a partial response but later converted to a CR with an additional 5 cycles of EV. The most common first subsequent treatment following EV/P was platinum-based chemotherapy (30.5%); 20.7% of patients achieved a response to subsequent platinum-based chemotherapy.

Coauthor of the trial Christof Vulsteke, MD, PhD, of Integrated Cancer Center, Ghent, in Belgium, recently spoke with Urology Times® about the implications of these findings for patients with la/mUC and the broader bladder cancer landscape.

Urology Times: How should practicing urologists interpret the durability of benefit seen with this combination compared with platinum-based chemotherapy?

Vulsteke: With 3½ years of median follow-up, [the combination of] enfortumab vedotin and pembrolizumab continues to demonstrate a superior overall survival benefit vs chemotherapy. That reinforces that enfortumab vedotin and pembrolizumab is the preferred standard of care for previously untreated locally advanced or metastatic urothelial carcinoma. This is a superior regimen and a very durable regimen. It's the best chance for your patients to have a long-term good outcome.

I think urologists will also ask about the toxicity. In the first 4 to 6 weeks, [the main concern is] skin toxicity. After that, then it's all about peripheral neuropathy. If you go on with this treatment, watch out [for] the peripheral neuropathy, but the other things like hyperglycemia, dry eyes, and blurred vision normally come very early. I think this is a very safe regimen, but you need experienced hands, and you have to be very careful with peripheral neuropathy in the long run.

Urology Times: The analysis also evaluated outcomes with subsequent therapies after progression. What insights do these data provide regarding sequencing strategies after frontline EV/P?

Vulsteke: A lot of trials are ongoing to assess what's the best regimen after enfortumab vedotin and pembrolizumab. This is such a good regimen, and it will be hard to beat the first line. In this trial, we have seen that the most frequent subsequent [first-line] therapy was platinum-containing chemotherapy. We showed that the chance of responding to carboplatin or cisplatin after EV/P was 20.7%, so it seems to be feasible after EV/P.

Urology Times: A key exploratory finding was that roughly two-thirds of patients who ultimately achieved a CR initially had only a partial response. How might this influence the way that clinicians think about treatment continuation and the timing of response assessment?

Vulsteke: The median time for achieving a complete response was 4.3 months, but if you look to the patients that first had a partial remission and then a complete remission, then the median time to complete remission is 6.6 months. You want to see some kind of response on the first assessment. [In total,] 67% of patients had some kind of response, either a PR or a CR. You can say to your patient [with an early partial response] that there's a good chance that you still will achieve a complete response, so don't stop at that time. Stick to the regimen, but be very careful about adverse effects. You cannot say that you will not achieve a complete response if you see the scan at 4 months. The median time for initial partial remission was around 2.1 months, so the patients are responding fast, but they continue to respond in the coming months.

Urology Times: Given the recent approval of this regimen in the perioperative setting for muscle-invasive bladder cancer, what do these long-term efficacy data suggest about the use of this regimen earlier in the disease course?

Vulsteke: You're touching on the trial that I was first author on, in the cis-ineligible [population], and then in the cis-eligible [population], it was Matt Galsky, [MD]. It's such a good regimen for bladder cancer, and I think it reinforces the shift of giving this early on in the course of disease for these patients. It reassures me that updated analyses will also be very good in the perioperative space.

Urology Times: Is there anything else that you’d like to add?

Vulsteke: What we have shown with 3½ years of median follow-up are some very good graphics to take into your practice and show your patients. Now you have a very good update for the long run and for toxicity. You can [show] a lot of these slides to your patients and say, "This is what you can expect, and this is what we have to be careful of."

REFERENCE

1. Powles T, Van Der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4507. doi:10.1200/JCO.2026.44.16_suppl.4507