EV+P maintains OS benefit at 3.5 years in metastatic UC

Updated results from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) at approximately 3.5 years of median follow-up continue to demonstrate a superior overall survival (OS) benefit with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) (EV+P) vs platinum-based chemotherapy as first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC), with deepening complete responses (CRs) and a consistent safety profile, according to data presented at the 2026 American Society of Clinical Oncology Annual Meeting.¹

Thomas B. Powles, MBBS, MRCP, MD, a professor of genitourinary oncology and director of the Barts Cancer Centre at St. Bartholomew's Hospital in London, United Kingdom, presented the findings. The updated analysis also included new exploratory data on subsequent therapy, CR evolution, and long-term treatment duration.

Background

EV-302/KEYNOTE-A39 established EV+P as a new first-line standard of care (SOC) for la/mUC based on significant improvements in both progression-free survival (PFS) and OS vs platinum-based chemotherapy.^1-3 The current analysis, with a data cut-off of October 6, 2025, evaluated longer-term efficacy and safety in the intention-to-treat (ITT) population at a median follow-up of 42.8 months, along with exploratory analyses in patients who achieved CR—either directly or after an initial partial response (PR)—and in patients who received EV+P for a duration of treatment (DOT) greater than 1 or 2 years. Blinded independent central review (BICR) was discontinued after a previous data cut-off; therefore, BICR-based end points were not updated for this analysis, although OS follow-up remains ongoing.

Study design

EV-302/KEYNOTE-A39 was a randomized, open-label phase 3 trial enrolling 886 patients with untreated la/mUC who were eligible for EV, pembrolizumab, and platinum-based chemotherapy, were PD-(L)1 inhibitor–naive, had a glomerular filtration rate of at least 30 mL/min, and had an ECOG performance status of 2 or lower. Patients were randomly assigned 1:1 to EV (1.25 mg/kg intravenously on days 1 and 8) plus pembrolizumab (200 mg intravenously on day 1) every 3 weeks until progression (EV+P arm; n=442) or gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (chemotherapy arm; n=444). Stratification factors were cisplatin eligibility, PD-L1 expression (combined positive score ≥10 vs <10), and presence of liver metastases. Dual primary end points were PFS by BICR and OS.

Updated overall survival

At a median follow-up of 42.8 months, median OS was 33.6 months (95% CI, 26.6–39.8) with EV+P (240 events/442 patients) vs 15.9 months (95% CI, 13.6–18.3) with chemotherapy (329 events/444 patients), corresponding to a stratified HR of 0.53 (95% CI, 0.45–0.63). At 3.5 years, an estimated 44.0% of patients in the EV+P arm remained alive vs 24.6% in the chemotherapy arm.

"The OS is maintained. The EV pembro tracks really nicely and plateaus around forty percent," Powles said, drawing a parallel to long-term survival data from an earlier-phase study. "I think this randomized phase 3 is probably going to end in the same place."

Subsequent therapy

Among EV+P-treated patients, 192 (43.4%) received subsequent anticancer therapy and 173 (39.1%) received subsequent systemic therapy. The most common first subsequent systemic therapy was platinum-containing chemotherapy in 135 patients (30.5%), comprising carboplatin-based therapy in 73 (16.5%) and cisplatin-based therapy in 61 (13.8%). PD-(L)1 inhibitor therapy was received by 17 patients (3.8%) as first subsequent systemic therapy.

Among evaluable patients in the EV+P arm who received subsequent platinum-based chemotherapy, the objective response rate (ORR) was 20.7% (28/135) overall, 19.7% (12/61) with cisplatin-based therapy, and 21.9% (16/73) with carboplatin-based therapy. Median OS from the start of platinum-based chemotherapy was 10.9 months (95% CI, 8.3–12.8).

"This is looking at those patients that got pembro—21% response rate. And there [is] no difference between gem-cis and gem-carbo," Powles said. "I suspect this probably becomes a standard of care."

In the chemotherapy arm, 324 patients (73.0%) received subsequent anticancer therapy, with PD-(L)1 inhibitor therapy as the most common first subsequent systemic treatment in 265 patients (59.7%), including maintenance therapy in 142 (32.0%), predominantly avelumab (Bavencio) in 135 (30.4%).

Objective response rates and CR evolution

In response-evaluable patients, ORR was 67.5% (295/437) with EV+P vs 44.2% (195/441) with chemotherapy. The CR rate was 30.4% (133/437) with EV+P vs 14.5% (64/441) with chemotherapy. Among patients with confirmed CR in the EV+P arm (n=133), 45 (10.3%) achieved CR directly and 88 (20.1%) converted from an initial PR to CR; 66.2% of patients with confirmed CR achieved it after initially achieving a PR.

Median time to CR among all EV+P patients who achieved CR was 4.3 months (interquartile range [IQR], 2.2–8.4). Among the 88 patients who converted from PR to CR, median time to initial PR was 2.1 months (IQR, 1.9–2.2) and median time to CR was 6.6 months (IQR, 4.3–12.1) from randomization. Cumulative CR data showed that patients continued to achieve CRs over time throughout the follow-up period, with CRs demonstrating long-term durability.

Baseline characteristics in the CR subgroups were generally consistent with the ITT population, with the exception that patients achieving CR directly as an initial response were more likely to have lymph node–only disease (51.1%) and less likely to have visceral metastases (35.6%) or liver metastases (6.7%) compared with the ITT population.

Outcomes in patients achieving CR

Among all EV+P patients achieving CR (n=133), median OS was not estimable (NE), with a 3.5-year OS rate of 83.6% (stratified HR vs chemotherapy CR patients [n=64], 0.36; 95% CI, 0.20–0.68). Among patients whose response converted from PR to CR (n=88 EV+P vs n=38 chemotherapy), median OS was also NE in the EV+P group vs 59.4 months (95% CI, 39.6–NE) in the chemotherapy group (stratified HR, 0.34; 95% CI, 0.15–0.77), with a 3.5-year OS rate of 82.4% vs 67.1%, respectively.

"The thought of having 30% of patients in CR, 85% of which are alive at 2 years, does suggest to us that we're curing some of these patients," Powles said. "And now maybe for the first time, really confident that we're doing that."

Treatment duration and dose modifications

In the overall EV+P safety population (n=440), median treatment duration was 12 cycles (range, 1–73) for EV and 9.6 months (range, 0.3–52) overall. At 6 months, 67.5% of patients remained on treatment; this declined to 41.8% at 12 months, 31.6% at 18 months, and 23.2% at 24 months. Among patients with DOT greater than 1 year (n=184), median EV duration was 14.5 months and median pembrolizumab duration was 24.1 months. Among those with DOT greater than 2 years (n=102), median EV duration was 22.3 months and median pembrolizumab duration was 24.9 months.

Treatment-related adverse events (TRAEs) leading to EV dose interruption occurred in 60.0% of patients in the overall population, rising to 75.5% in patients with DOT greater than 1 year and 74.5% in those with DOT greater than 2 years. TRAEs leading to EV dose reduction occurred in 43.0% of the overall population, 65.8% of those with DOT greater than 1 year, and 70.6% of those with DOT greater than 2 years. No dose reduction was permitted for pembrolizumab per protocol.

"If you want to keep patients on therapy, almost all my patients have dose reductions or dose interruptions. I think it's a really important part of what we do," Powles said.

Safety

The overall safety profile remained consistent with prior analyses. TRAEs of any grade occurred in 97.3% of patients overall, 99.5% of those with DOT greater than 1 year, and 100% of those with DOT greater than 2 years. Grade 3 or higher TRAEs occurred in 57.0%, 58.7%, and 57.8% of patients in these respective groups.

Among EV-related AEs of special interest, peripheral sensory neuropathy was present in approximately 60% of the overall population and approximately 85% to 88% of patients with longer DOT, with the largest observed increase (approximately 25%) attributed to cumulative monomethyl auristatin E (MMAE) exposure. Skin reactions occurred in approximately 67% overall and approximately 80% to 82% with longer DOT; grade 3 or higher skin reactions were observed in approximately 16% to 20% across groups. Modest increases in peripheral motor neuropathy, hyperglycemia, and dry eye were also noted with longer DOT, predominantly grade 1/2. No new safety signals were identified.

For pembrolizumab-related AEs of special interest, severe skin reactions, hypothyroidism, pneumonitis, and hyperthyroidism were the most commonly reported immune-related events. Hypothyroidism showed an increase with longer treatment duration. No new safety signals were identified for pembrolizumab with longer treatment exposure.

Conclusions

Powles concluded that with approximately 3.5 years of median follow-up, EV+P continues to demonstrate superior OS benefit reinforcing its role as the preferred SOC for first-line la/mUC. Platinum-based chemotherapy following EV+P was associated with clinically meaningful response rates, suggesting a potential role as a subsequent treatment standard. Cumulative responses deepened over time, with approximately two-thirds of patients with CR converting from PR, achieving similar survival rates to those with CR overall. Dose interruptions and reductions were described as important tools to manage AEs and facilitate continued therapy.

"EV pembro continues to be this transformative regime. I think it's curing patients," Powles said.

DISCLOSURES: Powles reported disclosures related to Astellas Pharma, AstraZeneca, BMS GmbH & Co, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson/Janssen, MashupMD, Merck, Merck Serono, Novartis, Pfizer, Roche, Seagen, MSD, and Bristol-Myers Squibb.

REFERENCES

1. Powles TB, van der Heijden M, 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; abstr 4507). doi:10.1200/JCO.2026.44.16_suppl.4507

2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

3. Powles T, Bellmunt J, Comperat E, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma Ann Oncol. 2024;35(6):485-490. doi:10.1016/j.annonc.2024.03.001

4. Witjes JA, Bruins MA, Carrión A, et al. European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2023 guidelines. Eur Urol. 2024;85(1):17-31. doi:10.1016/j.eururo.2023.08.016