The updated analysis of the phase III EV-302 trial continues to show the benefit of front-line enfortumab vedotin plus pembrolizumab (EV+P) compared with chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC).

“With 1 year of additional follow-up … front-line EV+P continues to maintain its transformative benefit over chemo in the broad patient population and across prespecified subgroups,” said lead study author Dr Thomas Powles from the Barts Cancer Centre, Queen Mary University of London in the UK, during his presentation at ASCO GU 2025.

In the overall cohort, the progression-free survival (PFS) benefit with the investigational regimen vs chemo was sustained after ~2.5 years of median follow-up (median 12.5 vs 6.3 months; stratified hazard ratio [HR], 0.48, 95 percent confidence interval [CI], 0.41?0.57; nominal two-sided p<0.00001).

Powles pointed out that the Kaplan-Meier curves diverged and stayed apart again and looked very similar to the previous data. “Now, [it appears] much more robust at 24 months, with PFS rates of 37.1 percent and 12.6 percent in the respective arms.”

The risk of death was nearly halved in the overall population with EV+P vs chemo (median overall survival [OS] 33.8 vs 15.9 months; stratified HR, 0.51, 95 percent CI, 0.43?0.61; nominal two-sided p<0.00001). [ASCO GU 2025, abstract 664]

“When we started looking at the median survival of these patients [before], we had 12?14 months; now, we have 34 months. I think a big difference has been made,” Powles stressed. “The [study] continues to show the compelling benefit of EV+P over chemo. The median OS of more than 2.5 years is unprecedented compared to what we have seen before.”

OS rates at 24 months were 60.1 percent and 35.4 percent for EV+P and chemo, respectively. This suggests that more patients on EV+P than on chemo were alive after starting treatment in the overall population, noted Powles and colleagues.

Both PFS and OS benefits were consistent across prespecified subgroups, with HRs ranging between 0.376 and 0.605 for PFS and 0.386 and 0.672 for OS. The benefits remained consistent irrespective of upper tract disease, liver metastases, PD-L1 expression, presence of metastatic disease, and renal function.

Of note, the OS benefit remained consistent with the overall cohort irrespective of cisplatin eligibility (median 36.7 vs 18.8 months; stratified HR, 0.54 [cisplatin eligible] and median 25.6 vs 12.7 months; stratified HR, 0.50 [cisplatin ineligible]).

Durable responses

The response to EV+P was durable, with a median duration of response (DoR) of 23.3 months. With chemo, the corresponding median DoR was only 7 months. Among responders without progressive disease or death, the probability of maintained response at 2 years was about 50 percent with EV+P and 24 percent with chemo.

“It is important to recognize that about 70 percent of [EV+P recipients] are responding, and [now about 50 percent] maintained their response at 2 years. Again, I think that is transformative,” said Powles.

Confirmed objective response rate was greater with the experimental regimen vs chemo (67.5 percent vs 44.2 percent; nominal two-sided p<0.00001). Of note, 30 percent of those on EV+P had complete response (CR) which, according to Powles, was also unparalleled in this setting. With chemo, the corresponding rate was only 14 percent.

Among patients with confirmed CR (cCR), there was a greater likelihood of remaining in cCR at 24 months with EV+P vs chemo (74.3 percent vs 43.2 percent; median duration of CR not reached vs 15.2 months). In this subset, the HRs for PFS and OS were 0.36 and 0.37, respectively, favouring the investigational regimen over chemo. The estimated 24-month PFS rates for EV+P and chemo were 78.2 percent and 53.7 percent, respectively; for OS, the corresponding rates were 95.4 percent and 85.8 percent.

“[Taken together,] these data suggest that patients in the EV+P arm continued to respond to treatment longer than those in the chemo arm. This was also true for the subgroup of patients with cCR, ie, those whose cancer was no longer detectable or seen on scans after treatment,” explained Powles and colleagues.

Transformative benefit

When looking at the most frequent treatment-related adverse events (TRAEs), the EV+P safety profile remained consistent with additional follow-up. According to Powles, there were no new safety signals, which is reassuring. The frequency and grade of TRAEs also aligned with the primary analysis, as did the treatment-related AEs of special interest.

In EV-302, 886 participants were randomized 1:1 to receive either EV+P or chemo. Pembrolizumab was administered for a maximum of 35 cycles; there were no maximum cycles for EV. Chemo (cisplatin or carboplatin plus gemcitabine) was given for a maximum of six cycles.

After a median follow-up of 29.1 months, 12 percent of EV+P recipients remained on treatment and none remained on chemo. At this timepoint, the fraction of participants in the respective arms who remained on study were 49 percent and 30 percent.

In the primary analysis, the investigational regimen nearly doubled the median PFS and median OS in front-line metastatic disease as opposed to platinum-based chemo, with high response rates. [N Engl J Med 2024;390:875-888]

“The [primary] findings resulted in transformative care across the world with approvals globally,” noted Powles. EV+P has become the preferred standard of care in global treatment guidelines for patients with untreated la/mUC. [Ann Oncol 2024;35:485-490; Eur Urol 2024;85:17-31]

“[The study results] are important for individuals who have a type of cancer that has spread over time beyond the place from where it first started in the urothelial cells lining the urinary tract to either nearby tissue or lymph nodes or to other parts of the body,” Powles and colleagues explained.

“EV+P should remain the standard of care in the front-line treatment of patients with la/mUC,” Powles concluded.