FDA Approves Durvalumab-Enfortumab Regimen Before Bladder Surgery

The FDA on Thursday approved perioperative durvalumab (Imfinzi; AstraZeneca) paired with three cycles of enfortumab vedotin, or EV (Padcev; Astellas), followed by single-agent durvalumab as adjuvant treatment after radical cystectomy. The regimen is for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy or who have refused it. AstraZeneca had said the approval would make this the first perioperative regimen giving EV only before surgery.

The green light rests on the phase 3 VOLGA trial. In cisplatin-ineligible or cisplatin-declining patients, the combination reduced the risk of recurrence, progression, failure to undergo surgery or death by 49%, and cut the risk of death by 42%, compared with surgery alone. Thomas Powles of Barts Cancer Institute in London presented the interim results October 24 at the European Society for Medical Oncology Congress 2026 in Madrid, with simultaneous publication in The New England Journal of Medicine.

“Patients with muscle-invasive bladder cancer require life-changing bladder removal surgery. Despite this, the cancer returns in about half of patients,” Powles said in a statement during ESMO. “A new regimen of perioperative durvalumab combined with enfortumab vedotin before surgery reduced the risk of death by 42%, with a manageable safety profile.” The FDA had granted priority review to AstraZeneca's supplemental Biologics License Application in September, with a decision expected in the fourth quarter of 2026.

About 1 in 4 bladder cancer patients has muscle-invasive disease, and up to half can't take cisplatin because of impaired kidney function or other conditions, according to the report. The field has shifted fast: NIAGARA established perioperative durvalumab plus neoadjuvant cisplatin chemotherapy for cisplatin-eligible patients, and in November 2025 the FDA approved perioperative EV plus pembrolizumab (Keytruda; Merck) for cisplatin-ineligible MIBC, extending it to cisplatin-eligible patients in July 2026. VOLGA asked a different question, testing EV concentrated before surgery while giving immunotherapy on both sides of cystectomy.

Between April 2022 and January 2025, 695 patients at 229 sites across 25 countries were randomized 1:1:1 to durvalumab-EV, durvalumab-tremelimumab-EV or cystectomy alone. Median age was 72; 76.1% were cisplatin-ineligible, most often for creatinine clearance under 60 mL/min, and 23.9% declined cisplatin. At a median follow-up of 22.9 months, estimated 24-month event-free survival was 63.5% with durvalumab-EV versus 45.1% with surgery alone, and median event-free survival was not reached versus 12.1 months. Estimated 24-month overall survival was 78.4% versus 69.4%, and pathologic complete response hit 45.1% versus 9.6%.

The triplet arm met its event-free survival endpoint with 24-month EFS of 60.1%, but its overall survival difference versus control was not significant. The authors wrote that “increasing treatment intensity may not necessarily improve outcomes in all patients,” citing higher toxicity and discontinuation with three drugs. Grade 3 or higher adverse events of any cause hit 71.1% on durvalumab-EV versus 50.2% of controls, with treatment-related grade 3-plus events at 30.7% and one treatment-related death (0.4%) from multiple organ dysfunction syndrome, against five (2.2%) in the triplet arm. Pruritus, urinary tract infection, anemia and diarrhea were most common; EV-related skin reactions occurred in 48.7% and peripheral neuropathy in 17.5%. The authors reported no new safety signals. Adherence figures matter to payers: 97.9% of durvalumab-EV patients started neoadjuvant treatment and 84.2% finished it, cystectomy rates were 85.0% versus 78.6%, and 67.4% started adjuvant durvalumab with 54.9% completing it. Subsequent anticancer therapy went to 12.9% of the durvalumab-EV group versus 28.4% of controls. EV exposure totals three cycles here, against nine in the approved EV-pembrolizumab regimen, and the two have never been compared head to head.