In the phase III VOLGA trial, researchers evaluated the use of perioperative durvalumab, with or without tremelimumab, plus neoadjuvant enfortumab vedotin vs radical cystectomy alone in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy. Researchers reported significantly improved event-free survival with both experimental regimens compared with radical cystectomy alone. Overall survival was also significantly improved with durvalumab plus enfortumab vedotin without tremelimumab, but not with the three-drug regimen.The findings were presented during the European Society for Medical Oncology (ESMO) Congress 2026 (Abstract LBA2) and simultaneously published by Powles et al in The New England Journal of Medicine.
Study Details
The international, open-label VOLGA trial enrolled 695 patients with muscle-invasive bladder cancer at 229 sites in 25 countries between April 2022 and January 2025. Patients were medically fit for radical cystectomy but were either ineligible for or declined cisplatin-based chemotherapy. They were randomly assigned 1:1:1 to receive perioperative durvalumab plus neoadjuvant enfortumab vedotin (n = 233), the same regimen with tremelimumab (n = 233), or radical cystectomy alone (n = 229).
Patients in the durvalumab/enfortumab vedotin group (two-drug group) received three 21-day cycles of neoadjuvant treatment, including durvalumab on day 1 of each cycle and enfortumab vedotin on days 1 and 8 of each cycle. This was followed by radical cystectomy and nine 28-day cycles of adjuvant durvalumab (day 1 of each cycle).
Patients in the three-drug group (durvalumab/enfortumab vedotin/tremelimumab) received the same regimen plus neoadjuvant tremelimumab (on day 1 of cycle 1 and day 8 of cycle 2), followed by radical cystectomy and nine 28-day cycles of adjuvant durvalumab (day 1 of each cycle) plus adjuvant tremelimumab on day 1 of cycle 1 only.
The dual primary endpoints were event-free survival with each experimental regimen vs surgery alone; the key secondary endpoint was overall survival.
Key Results
At the prespecified interim analysis (data cutoff, March 2, 2026), median event-free survival follow-up was 22.9 months. Estimated 24-month event-free survival was 63.5% with durvalumab/enfortumab vedotin vs 45.1% with surgery alone (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.38–0.67; P < .001). Estimated 24-month overall survival was 78.4% vs 69.4%, respectively (HR = 0.58, 95% CI = 0.40–0.83; P = .003). Both differences were statistically significant.
With the three-drug regimen, estimated 24-month event-free survival was 60.1% vs 45.1% with surgery alone (HR = 0.61, 95% CI = 0.47–0.80; P < .001). However, the overall survival difference was not statistically significant (HR = 0.77, 95% CI = 0.54–1.07; P = .12), and follow-up is ongoing.
Pathologic complete response rates were 45.1% with durvalumab/enfortumab vedotin, 42.9% with the three-drug regimen, and 9.6% with surgery alone.
Radical cystectomy was completed in 85.0% of the two-drug group, 78.5% of the three-drug group, and 78.6% in the group of patients randomized to receive surgery alone. Adjuvant treatment was completed by 54.9% and 42.1% of patients receiving the two- and three-drug regimens, respectively.
Grade 3 or higher adverse events of any cause occurred in 71.1%, 79.5%, and 50.2% of patients, respectively. Treatment-related grade 3 or higher adverse events occurred in 30.7% and 44.5% of patients receiving the two- and three-drug regimens, respectively. Treatment-related adverse events resulted in one death in the two-drug group (multiple-organ dysfunction syndrome) and five deaths in the three-drug group (pneumonia aspiration [n = 1], myasthenia gravis [n = 1], myocarditis [n = 1], immune-mediated lung disease [n = 1], and Stevens–Johnson syndrome [n = 1]).
The investigators concluded: “Perioperative durvalumab with or without tremelimumab plus three cycles of neoadjuvant enfortumab vedotin resulted in significantly better event-free survival outcomes than surgery alone. Perioperative durvalumab plus enfortumab vedotin led to significantly better overall survival outcomes than surgery alone. Grade 3 or higher adverse events of any cause were noted in more than half the patients in the durvalumab groups.”
Thomas Powles, MD, of Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust Biomedical Research Centre, London, is the corresponding author for the New England Journal of Medicine article.
DISCLOSURE: The study was supported by AstraZeneca. For full disclosures of the study authors, visit nejm.org.
