FDA Approves Durvalumab Plus EV Before Surgery in Cisplatin-Ineligible MIBC

FDA today approved perioperative durvalumab (Imfinzi; AstraZeneca) combined with 3 cycles of enfortumab vedotin, or EV (Padcev; Astellas) followed by single-agent durvalumab as adjuvant treatment after radical cystectomy, for the treatment of adult patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or who have refused cisplatin-based chemotherapy.¹

Approval is based on the phase 3 VOLGA trial (NCT04960709).² The study showed that the combination regimen, given before bladder removal, 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 in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or declined cisplatin.

Thomas Powles, MBBS, MRCP, MD, chair and professor of Genitourinary Oncology at Barts Cancer Institute in London, presented the interim results October 24 during the Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain; they were published simultaneously in The New England Journal of Medicine (NEJM).^2,3 In September, the FDA had granted priority review to AstraZeneca's supplemental Biologics License Application for the regimen, with a decision expected in the fourth quarter of 2026.^4,5

“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. These practice-changing results support this approach as a patient centric, potential new standard of care in this setting.”

A Rapidly Changing Landscape

About 1 in 4 patients with bladder cancer has muscle-invasive disease, and up to half of patients are ineligible for cisplatin because of impaired kidney function or comorbidities.⁴ For these patients, radical cystectomy alone was long the standard of care, despite high rates of recurrence and a poor prognosis.⁴

The past 2 years have brought a revolution in treatment for these patients. For those who are cisplatin eligible, the NIAGARA trial established perioperative durvalumab plus neoadjuvant cisplatin-based chemotherapy as a standard of care.⁶ Then EV, a nectin-4–directed antibody-drug conjugate (ADC), moved into the curative setting. In November 2025, the FDA approved perioperative EV plus pembrolizumab (Keytruda; Merck) for cisplatin-ineligible MIBC based on KEYNOTE-905/EV-303, and in July 2026 the agency extended the indication to cisplatin-eligible patients based on KEYNOTE-B15/EV-304.^7-10 In that regimen, EV is given for 3 cycles before surgery and 6 cycles after, and adjuvant treatment lasts 42 weeks in total.⁸

The VOLGA trial asked a different question. In the NEJM article, investigators write that the appropriate timing and duration of EV, including whether postoperative treatment is necessary, remains uncertain. Their regimen concentrates EV before the stress of surgery while giving immunotherapy on both sides of cystectomy.² AstraZeneca officials said at the time that the aprpoval would be the first perioperative regimen with EV given only before surgery.⁵

“VOLGA is clearly a positive trial in line with the KEYNOTE-905/EV-303 trial of EV plus pembrolizumab in the cisplatin-ineligible setting,” Michiel van der Heijden of the Netherlands Cancer Institute in Amsterdam said in comments published by ESMO. He added that further investigation is needed to determine whether EV should be used in the adjuvant setting.¹¹

Trial Design and Efficacy

Between April 2022 and January 2025, 695 patients at 229 sites in 25 countries were randomly assigned 1:1:1 to durvalumab-EV, durvalumab-tremelimumab (Imjudo; AstraZeneca)-EV, or cystectomy alone, with locally approved adjuvant therapy permitted in the control arm.² In the durvalumab-EV arm, patients received durvalumab 1500 mg plus EV 1.25 mg/kg for three 21-day cycles, followed by cystectomy and 9 cycles of adjuvant durvalumab every 4 weeks. Median age was 72 years; 76.1% of patients were cisplatin-ineligible, most often because of creatinine clearance below 60 mL/min, and 23.9% declined cisplatin.²

At a median follow-up of 22.9 months, estimated 24-month event-free survival (EFS) was 63.5% with durvalumab-EV vs 45.1% with surgery alone (HR, 0.51; 95% CI, 0.38-0.67; P < .001). Median EFS was not reached vs 12.1 months.^1,3 Estimated 24-month overall survival (OS) was 78.4% vs 69.4% (HR, 0.58; 95% CI, 0.40-0.83; P = .003). Pathologic complete response by local review occurred in 45.1% vs 9.6% of patients.²

The triplet arm also met its EFS end point (24-month EFS, 60.1%; HR, 0.61; 95% CI, 0.47-0.80), but the OS difference vs control was not significant (HR, 0.77; 95% CI, 0.54-1.07; P = .12). Given higher rates of toxicity and discontinuation with 3 drugs, the authors wrote that “increasing treatment intensity may not necessarily improve outcomes in all patients.” Follow-up is ongoing.²

Adverse Events

Grade 3 or higher adverse events (AEs) of any cause occurred in 71.1% of patients in the durvalumab-EV arm vs 50.2% of controls; treatment-related grade 3 or higher events occurred in 30.7%.² There was 1 treatment-related death (0.4%) in the durvalumab-EV arm, from multiple organ dysfunction syndrome, and 5 (2.2%) in the triplet arm.²

The most common AEs with durvalumab-EV were pruritus (43.9%), urinary tract infection (36.4%), anemia (32.0%), and diarrhea (26.3%). Among treatment-related events associated with EV, skin reactions occurred in 48.7% of patients (grade 3-4, 4.8%) and peripheral neuropathy in 17.5%, with a single grade 3 case (0.4%). Grade 3-4 hyperglycemia occurred in 3.9%, and immune-mediated AEs of any grade occurred in 32.9%.² The authors acknowledged that most patients had grade 3 or higher AEs but reported no new safety signals.²

Adherence and Outcomes of Interest to Payers

Several findings speak to feasibility and resource use. Of patients assigned to durvalumab-EV, 97.9% began neoadjuvant treatment and 84.2% completed it.² Cystectomy rates were 85.0% vs 78.6% in the control arm, where patient decision kept 13.1% from surgery, vs 6.4% in the durvalumab-EV group. Median time from the last neoadjuvant dose to surgery was 42 days, and AEs led to surgery cancellation in 0.9% of patients and delay in 3.5%. Surgery-related AEs within 90 days occurred in 60.1% vs 67.6% of controls.²

Adherence dropped after surgery: 67.4% of patients started adjuvant durvalumab and 54.9% completed it. AEs led to discontinuation of any treatment in 21.1% overall, including 11.5% during the adjuvant phase.²

Downstream care also differed. Subsequent anticancer therapy was given to 12.9% of patients in the durvalumab-EV group after trial treatment ended vs 28.4% of controls.² Only 14.4% of controls received adjuvant therapy, most often nivolumab, and the authors cited regional variability in access to adjuvant nivolumab as a limitation on the applicability of the control arm.¹

Patient-reported quality of life was maintained, with no clinically meaningful decline from baseline; however, questionnaire completion rates were low, particularly in the control arm.²

For payers, a defining feature is EV exposure: 3 cycles in total, vs 9 in the approved EV-pembrolizumab regimen, alongside fixed-dose durvalumab every 4 weeks after surgery.^1,8 The regimens have not been compared head to head, and VOLGA's open-label design and evolving control arm limit cross-trial comparisons.²

What's Next for ADCs

“Data on ADCs plus immune checkpoint inhibitors in bladder cancer are now robust and consistent, whereas immune checkpoint inhibitors and chemotherapy in bladder cancer have shown less consistency, given the negative results presented at the Congress,” van der Heijden said in the ESMO briefing. He noted that sacituzumab govitecan (Trodelvy; Gilead) did not significantly improve survival in TROPiCS-04, while data on HER2-directed disitamab vedotin, taken together with EV results, suggest the vedotin payload is particularly active in urothelial cancer.¹¹

References

1. FDA approves durvalumab with enfortumab vedotin for muscle invasive bladder cancer. The ASCO Post. November 13, 2026. Accessed November 13, 2026. https://ascopost.com/news/november-2026/fda-approves-durvalumab-with-enfortumab-vedotin-ejfv-for-muscle-invasive-bladder-cancer/
2. Powles T, Grande E, Simone G, et al. Durvalumab, tremelimumab, and enfortumab vedotin in muscle-invasive bladder cancer. N Engl J Med. Published online October 24, 2026. doi:10.1056/NEJMoa2608323
3. Powles TB, Grande E, Simone G, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA2. https://cslide.ctimeetingtech.com/esmo2026/attendee/confcal/show/session/346
4. Perioperative Imfinzi plus neoadjuvant enfortumab vedotin reduced risk of recurrence by 49% and risk of death by 42% in muscle-invasive bladder cancer. News release. AstraZeneca. October 24, 2026. Accessed November 13, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/perioperative-imfinzi-plus-neoadjuvant-enfortumab-vedotin-reduced-risk-of-recurrence-by-49-and-risk-of-death-by-42-in-muscle-invasive-bladder-cancer.html
5. Perioperative Imfinzi plus neoadjuvant enfortumab vedotin granted priority review in the US for patients with muscle-invasive bladder cancer. News release. AstraZeneca. September 25, 2026. Accessed November 13, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/perioperative-imfinzi-plus-neoadjuvant-enfortumab-vedotin-granted-priority-review-in-the-us-for-patients-with-muscle-invasive-bladder-cancer.html
6. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391(19):1773-1786.doi:10.1056/NEJMoa2408154
7. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. DOI: 10.1056/NEJMoa2511674
8. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed November 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
9. Galsky MD, Valderrama BP, Maruzzo M, et al. Enfortumab vedotin and pembrolizumab in cisplatin-eligible bladder cancer. N Engl J Med. 2026;395(4):338-348. doi:10.1056/NEJMoa2601486
10. FDA OKs pembrolizumab/EV combo in muscle invasive bladder cancer. CancerNetwork. July 10, 2026. Accessed November 13, 2026. https://www.cancernetwork.com/view/fda-oks-pembrolizumab-ev-combo-in-muscle-invasive-bladder-cancer
11. Results from VOLGA show that antibody–drug conjugates continue to increase treatment options for muscle-invasive bladder cancer. ESMO. October 24, 2026. Accessed November 13, 2026. https://www.esmo.org/insights-by-esmo/all-news/neoadjuvant-enfortumab-vedotin-added-to-peri-operative-durvalumab-significantly-improved-event-free-and-overall-survival