In previously untreated patients with locally advanced or metastatic urothelial carcinoma, use of the antibody-drug conjugate enfortumab vedotin-ejfv in combination with the PD-1 inhibitor pembrolizumab continues to demonstrate a significant survival benefit over chemotherapy, according to updated data presented at the 2025 ASCO Genitourinary Cancers Symposium.1
Additional follow-up data from the phase III EV-302 trial, which evaluated enfortumab vedotin plus pembrolizumab as a first-line treatment in metastatic urothelial carcinoma compared with standard platinum-based chemotherapy, showed a 60% survival rate at 2 years vs 35% in the control arm. With a median follow-up of 29.1 months, the updated results reinforce the previously reported benefit of this combination therapy.
“With a median overall survival of 34 months, we continue to see unprecedented outcomes in metastatic urothelial carcinoma [with enfortumab vedotin plus pembrolizumab].”— Thomas Powles, MD
Tweet this quote
“With a median overall survival of 34 months, we continue to see unprecedented outcomes in metastatic urothelial carcinoma,” said lead study author Thomas Powles, MD, Professor of Oncology, Barts Cancer Institute, London. “These data further solidify enfortumab vedotin plus pembrolizumab as the preferred front-line therapy.”
Study Methods
EV-302 is a global, randomized phase III trial comparing enfortumab vedotin plus pembrolizumab with platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in the front-line setting for locally advanced or metastatic urothelial carcinoma. A total of 886 patients were randomly assigned 1:1, with 442 receiving enfortumab vedotin plus pembrolizumab and 444 receiving chemotherapy. Patients in the chemotherapy arm received up to six cycles of treatment, with 30% also receiving maintenance therapy with the monoclonal antibody avelumab.
The updated analysis includes an additional year of follow-up, extending beyond the initial 13-month report. Among study participants, 12% of patients remain on
enfortumab vedotin plus pembrolizumab, whereas no patients remain on chemotherapy beyond the six cycles. A total of 49% of patients given enfortumab vedotin plus pembrolizumab remain on study, compared with 30% of the control arm. The study population included patients with liver metastases, upper tract disease, and varying PD-L1 expression levels.
Key Results
As Dr. Powles reported, enfortumab vedotin plus pembrolizumab maintained a substantial progression-free survival benefit over chemotherapy (hazard ratio [HR] = 0.48). The 24-month progression-free survival rate was 37% vs 12%, said Dr. Powles, demonstrating consistency with prior reports. Overall survival also remained significantly improved, with a hazard ratio of 0.51 and a survival rate of 60% vs 35% at 2 years.
“Median overall survival now stands at 34 months, a remarkable improvement compared to historical benchmarks of 12 to 14 months in metastatic urothelial carcinoma,” said Dr. Powles. He noted the benefit was observed across all subgroups, regardless of PD-L1 status, renal function, liver metastases, or platinum eligibility.
In the response-evaluable population, the confirmed objective response rate was 67.5% with enfortumab vedotin plus pembrolizumab vs 44.2% with chemotherapy. The median duration of response was 23.3 months for enfortumab vedotin plus pembrolizumab compared with 7.0 months for chemotherapy.
Among patients achieving a complete confirmed response, 30.4% were given enfortumab vedotin plus pembrolizumab vs 14.5% on the chemotherapy arm. The median duration of complete confirmed response was not reached with enfortumab vedotin plus pembrolizumab, compared with 15.2 months for chemotherapy.
The safety profile of enfortumab vedotin plus pembrolizumab also remained consistent with prior reports, according to Dr. Powles. Grade 3 or 4 adverse events occurred in 57.3% of patients receiving enfortumab vedotin plus pembrolizumab compared with 69.5% of those receiving chemotherapy.
In the subgroup with complete confirmed response, grade 3 or 4 treatment-related adverse events occurred in 61.7% vs 71.9%, respectively. The rate of treatment-related deaths was 1.1% with enfortumab vedotin plus pembrolizumab and 0.9% with chemotherapy; no treatment-related deaths occurred in the subgroup with complete confirmed response.
According to Dr. Powles, the updated findings reinforce enfortumab vedotin plus pembrolizumab as the new standard of care in the first-line setting for locally advanced or metastatic urothelial carcinoma. “The sustained overall survival and progression-free survival benefits, along with high response rates and manageable toxicity, make this combination a compelling alternative to traditional chemotherapy,” said Dr. Powles. “The study’s long-term data provide further confidence in the durability of response and overall treatment benefit.”
Additional research will further explore optimization strategies for toxicity management and treatment sequencing.
DISCLOSURE: Dr. Powles reported financial relationships with Astellas Pharma, AstraZeneca, BMS, GmbH & Co. KG, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Janssen, MashupMD, Merck, Merck Serono, Novartis, Pfizer, Roche, Seagen, and MSD.
REFERENCE
1. Powles T, Van Der Heijden M, Loriot Y, et al: EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. 2025 ASCO Genitourinary Cancers Symposium. Abstract 664. Presented February 14, 2025.
EXPERT POINT OF VIEW
Julian Hong, MD, MS, Associate Professor in Residence at the Department of Radiation Oncology and Bakar Computational Health Sciences Institute, University of California, San Francisco, highlighted the long-term significance of the updated EV-302 trial data and its impact on front-line treatment decisions for urothelial carcinoma.
Julian Hong, MD, MS
“The updated analysis, with follow-up beyond 2.5 years, reinforces the durability of the benefits initially observed in the phase III study, which has already influenced standard-of-care treatment approaches,” Dr. Hong told The ASCO Post. “The original findings were crucial in defining front-line treatment decisions, and these updated data give us more confidence that the results in the original report continue to be maintained over more time.”
Questions Remain
Although the long-term data solidify the role of enfortumab vedotin-ejfv plus pembrolizumab in the front-line setting, Dr. Hong emphasized that several questions remain regarding treatment sequencing and patient eligibility. Of note, further research is needed to determine optimal second-line therapies after enfortumab vedotin plus pembrolizumab, as well as strategies for patients who may not be eligible for this combination.
Dr. Hong also expressed particular interest in how these findings might translate into earlier-stage urothelial carcinoma treatment settings. He suggested that the demonstrated durability of response may have implications for future clinical trials involving localized or locally advanced disease. “As a radiation oncologist, I am looking forward to how these findings may translate into earlier-stage settings,” he concluded. “Of course, we are always hoping to make more progress.”
DISCLOSURE: Dr. Hong has received research funding from Roche.
