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For patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC), the combination of enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) (EV+P) continued to provide significant efficacy benefits compared with chemotherapy, new follow-up data from the EV-302 trial showed.

“The take-home message is that enfortumab-vedotin and pembrolizumab together in the frontline setting in metastatic urothelial cancer continues to maintain its transformative benefit over chemotherapy,” said Thomas B. Powles, MBBS, MRCP, MD, from Barts Cancer Institute at Queen Mary University, London, England.

Powles presented updated data from the EV-302 trial at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium (GUCS) 2025, held in San Francisco.

Doubling of Progression-free survival (PFS), Overall Survival (OS)

In EV-302, patients with previously untreated la/mUC were stratified by cisplatin eligibility, programmed death protein-1 ligand-1 expression levels, and presence or absence of liver metastases and then randomized to EV+P with no maximum number of cycles of enfortumab vedotin but a maximum of 35 cycles of pembrolizumab or to platinum-based chemotherapy with gemcitabine.

The primary analysis of the trial showed that after a median follow-up for survival of 17.2 months, the median PFS was 12.5 months for patients randomized to the antibody-drug conjugate (ADC) EV+P vs 6.3 months for those randomized to chemotherapy with cisplatin or carboplatin plus gemcitabine, translating into a hazard ratio for EV+P of 0.45 (P < .001).

Also in the primary analysis, median OS was 31.5 months for patients assigned to EV+P vs 16.1 months for those randomized to chemotherapy, translating into a hazard ratio for death with the combination of 0.47 (P < .001).

Updated Results

At ASCO GU 2025, Powles reported that after 29.1 months of median follow-up, 12% of patients randomized to EV+P remained on the regimen, whereas no patients randomized to chemotherapy were still on chemotherapy. In all, 49% of patients assigned to EV+P and 30% assigned to chemotherapy were still being followed on study as of the August 8, 2024, data cutoff.

The benefit of EV+P compared with chemotherapy has remained consistent, Powles said, with respective 1- and 2-year PFS rates of 51.4% and 37.1% compared with 21.7% and 12.6% with chemotherapy.

Similarly, 1- and 2-year OS rates also favored the ADC/immunotherapy combination at 77.7% and 60.1% vs 61.1% and 35.4%, respectively.

The OS benefit with EV+P was consistent both in patients who were deemed to be cisplatin eligible at enrollment as well as in patients deemed cisplatin ineligible.

The duration of response with EV+P was also noteworthy, Powles said.

“It’s important to recognize that about 70% of these patients are responding, and they maintained their response at 2 years. Again, in my opinion, I think that’s transformative,” he said.

In all, 30% of patients on EV+P had complete responses compared with 14% of those on chemotherapy. As an analysis of duration of confirmed complete responses showed, 74.3% of patients assigned to EV+P remained in complete response at 2 years compared with 43.2% of patients randomized to chemotherapy.

The safety profile of each study group remained consistent, with no new safety signals after 1 additional year of follow-up. The most frequent treatment-related adverse events occurring in 20% or more of patients were peripheral sensory neuropathy, pruritus, alopecia, macropapular rash, fatigue, diarrhea, decreased appetite, and nausea.

“These data reinforce enfortumab vedotin and pembrolizumab as a new standard of care in frontline urothelial cancer,” Powles concluded.

How Long?

In the Q&A following the presentation, Parminder Singh, MD, from the Mayo Clinic in Phoenix, asked Powles whether the durability of responses for patients on EV+P could be a predictor of duration of therapy once they achieved radiologic complete responses.

“What we see in my clinic is patients who have had transformative outcomes, who were told they had a lethal disease, and are in either durable complete or partial response, and some of them are going on for years. We do need to address this issue of how long we should be giving therapy for,” Powles replied.

He added that while a randomized trial might help to answer the question of treatment duration, many of his patients are reluctant to go off therapy, and therefore it might be difficult to recruit enough patients for such a study. He suggested instead an observational approach with consensus among caregivers to determine the optimum length of therapy.

“My gut feeling on this is 5 years is too long. I think we’d all agree on that. I think a year or 6 months feels too short for me. I think while patients are tolerating treatment well, in CR [controlled release], I feel 2 years for me, that seems like quite a long time to be honest,” he said. 

EV-302/KEYNOTE A-39 was funded by Astellas Pharma, Merck Sharp & Dohme, and Seagen. Powles disclosed receiving consulting/advisory roles with those companies and others, travel and accommodation expenses from Merck and others, and institutional research funding from those companies and others. Singh had disclosed receiving honoraria from Curio Science, and MedPage Today/ASCO, consulting/advisory roles for Janssen Oncology, EMD Serono, Aveo, Bayer, and ImmunityBio, and an uncompensated relationship with Seagen.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape Medical News.