Durvalumab-EV Perioperative Regimen Receives FDA Priority Review in MIBC

The FDA granted priority review to a supplemental biologics license application (sBLA) for durvalumab (Imfinzi) in combination with enfortumab vedotin (EV; Padcev) for the treatment of patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or have declined cisplatin-based chemotherapy. The Prescription Drug User Fee Act (PDUFA) action date is anticipated during the fourth quarter of 2026.¹

The application is based on results from the phase 3 VOLGA trial (NCT04960709). A planned interim analysis showed that perioperative durvalumab combined with neoadjuvant EV led to statistically significant and clinically meaningful improvements in event-free survival (EFS) and overall survival (OS) compared with radical cystectomy, with or without approved adjuvant treatment. The safety and tolerability of durvalumab plus EV were reported as consistent with the known safety profiles of the individual agents, with no new safety signals identified.

“This [p]riority [r]eview reinforces the potential of [durvalumab] to become the immunotherapy backbone treatment for [MIBC], where patients face high rates of recurrence despite bladder removal surgery,” Susan Galbraith, MD, PhD, executive vice president, oncology hematology research and development at AstraZeneca, stated in the news release. “If approved, this would be the first perioperative regimen with enfortumab vedotin given only before surgery; a potentially new standard of care offering practice-changing efficacy and tolerability in this curative-intent setting.”

Trial Design and Preliminary Findings

VOLGA is a phase 3, randomized, open-label, multicenter global trial conducted at 182 centers across 25 countries in Europe, North America, South America, and Asia. The trial randomly assigned 695 patients undergoing radical cystectomy who were ineligible for or had declined cisplatin 1:1:1 to 1 of 3 arms: durvalumab plus EV plus tremelimumab (Imjudo) before surgery, followed by adjuvant durvalumab plus a single cycle of tremelimumab (arm 1); durvalumab plus EV before surgery, followed by adjuvant durvalumab monotherapy (arm 2); or radical cystectomy with or without approved adjuvant therapy as the comparator (arm 3). Arm 1 received 3 cycles of durvalumab and EV plus 2 cycles of tremelimumab preoperatively, followed by 9 cycles of adjuvant durvalumab plus 1 cycle of tremelimumab; arm 2 received 3 cycles of durvalumab and EV preoperatively, followed by 9 cycles of adjuvant durvalumab monotherapy.

The trial's dual primary end points are EFS for the 2 experimental arms vs the comparator arm, defined as time from randomization to first recurrence following radical cystectomy, first progression in patients who did not undergo radical cystectomy, failure to undergo radical cystectomy in patients with residual disease, or death from any cause. Secondary end points include OS in arm 1 vs arm 3 and arm 2 vs arm 3, pathologic complete response, disease-free survival, and pathologic downstaging in both experimental arms. Applications to regulators based on VOLGA data are currently under review in the European Union, Japan, and several other countries.

In an exploratory analysis from the safety run-in of VOLGA, circulating tumor DNA clearance was associated with improved clinical outcomes including pathologic response and EFS which could help determine the appropriate patients for escalation or deescalation of therapy.²

Disease and Setting Background

Approximately 1 in 4 patients with bladder cancer has MIBC.¹ Historically, the standard treatment for cisplatin-ineligible patients with MIBC, who make up as many as 50% of patients in this setting, has been radical cystectomy alone, but approximately 50% of patients who undergo bladder removal experience disease recurrence.

EV plus pembrolizumab (Keytruda) was approved in the perioperative setting for MIBC based on KEYNOTE-905 (NCT03924895); the estimated 2-year EFS was 74.7% with EV/pembrolizumab vs 39.4% in the control group (HR, 0.40; 95% CI, 0.28-0.57; P <.001) whereas OS was 79.7% vs 63.1%, respectively (HR, 0.50; 95% CI, 0.33-0.74; P <.001).³

REFERENCES

1. 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 September 25, 2026. https://tinyurl.com/mrxev892

2. Drakaki A, Powles TB, Wang Y, et al. Circulating tumor DNA (ctDNA) clearance with neoadjuvant durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) for cisplatin-ineligible muscle-invasive bladder cancer (MIBC) from the safety run-in cohort of the phase 3 VOLGA trial. Presented at: 2024 European Society for Medical Oncology Congress. September 13-17, 2024. Barcelona, Spain. Abstract 1970MO.

3. Vulsteke C, Adra N, Danchaivijitr P, et al; KENYOTE-905/EV-303 Investigators. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674