EV-302: Updated Analysis Reinforces Enfortumab Vedotin Plus Pembrolizumab as Standard of Care in Advanced Urothelial Carcinoma

A newly updated analysis from the EV-302/KEYNOTE-A39 trial continues to demonstrate superior efficacy and durable responses with enfortumab vedotin (EV) plus pembrolizumab (P) compared with standard chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). The findings, presented by Thomas Powles, MBBS, MD, of Barts Cancer Centre, at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, include more than two years of median follow-up and an exploratory analysis of patients who achieved a confirmed complete response (cCR).

EV-302 is a phase III global randomized trial comparing EV+P with platinum-based chemotherapy as first-line therapy for patients with previously untreated la/mUC. The trial’s dual primary endpoints were progression-free survival (PFS) and overall survival (OS), both assessed by blinded independent central review. Secondary endpoints included confirmed objective response rate, duration of response (DOR), and safety; an exploratory analysis evaluated outcomes in patients with cCR.

Patients were randomized 1:1 to receive either EV (1.25 mg/kg on days 1 and 8) + P (200 mg on day 1) or standard chemotherapy (gemcitabine with cisplatin or carboplatin) every three weeks.

With a median follow-up of 29.1 months, EV+P continued to outperform chemotherapy in all major efficacy endpoints. Median PFS was 12.5 months with EV+P versus 6.3 months with chemotherapy (hazard ratio [HR], 0.48; 95% CI, 0.41-0.57), reflecting a 52% reduction in the risk of progression or death. Median OS was 33.8 months with EV+P compared with 15.9 months with chemotherapy (HR, 0.51; 95% CI, 0.43-0.61), confirming a 49% reduction in the risk of death.

Overall survival benefit was observed regardless of cisplatin eligibility or the presence of liver metastases. In cisplatin-eligible patients, median OS was 36.7 months with EV+P versus 18.7 months with chemotherapy (HR, 0.54), and in cisplatin-ineligible patients, OS was 25.6 months with EV+P versus 12.7 months with chemotherapy (HR, 0.50). Patients with liver metastases, a subgroup historically associated with poor prognosis, also experienced a significant OS benefit (19.1 months with EV+P vs 10.1 months with chemotherapy; HR, 0.56).

In the response-evaluable population, confirmed ORR was 67.5% with EV+P versus 44.2% with chemotherapy. Median DOR was 23.3 months with EV+P versus 7.0 months with chemotherapy, suggesting greater durability of response with the combination regimen.

Among patients who achieved a cCR, 30.4% in the EV+P arm and 14.5% in the chemotherapy arm achieved a cCR, indicating more than double the rate of complete tumor clearance with the combination therapy. Notably, the median duration of cCR was not reached in the EV+P arm, whereas it was 15.2 months in the chemotherapy arm, suggesting that responses with EV+P were not only more frequent but also longer lasting.

The updated safety analysis confirmed that EV+P maintains a favorable risk-benefit profile, with no new safety signals emerging. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 57.3% of patients receiving EV+P versus 69.5% of those receiving chemotherapy, reinforcing that EV+P had a lower incidence of severe toxicity than chemotherapy. In the cCR subgroup, TRAEs were reported in 61.7% of EV+P-treated patients compared with 71.9% of chemotherapy-treated patients.

Treatment-related deaths were low in both arms, occurring in 1.1% of patients in the EV+P group and 0.9% in the chemotherapy group. No treatment-related deaths were reported among patients who achieved a complete response in either arm.

Clinical Implications

These results reaffirm EV+P as the standard of care (SOC) for first-line treatment of la/mUC, as recognized in global treatment guidelines. The updated analysis highlights the long-term efficacy and durability of responses with EV+P, particularly in patients achieving complete responses, where the duration of cCR remains unreached. Given the consistent benefit across patient subgroups, including those with cisplatin-ineligible disease and liver metastases, these findings further support the broad applicability of EV+P in urothelial carcinoma treatment.