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VOLGA: perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in MIBC

The treatment of muscle-invasive bladder cancer (MIBC) has long been defined by radical cystectomy and neoadjuvant platinum-based chemotherapy, which are associated with high long-term toxicity and a substantial risk of relapse. As a result, alternative perioperative strategies have been developed, including targeted therapies, antibody-drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs), reducing the use of cisplatin chemotherapy.1 Durvalumab, an anti-PD-L1 ICI, and enfortumab vedotin (EV), a Nectin-4-targeting ADC, are both established separately as perioperative treatments for MIBC.2

The Phase III VOLGA (NCT04960709) trial, presented at the 2026 European Society for Medical Oncology (ESMO) Congress, investigated the combination of durvalumab and EV, with or without the anti-CTLA-4 ICI tremelimumab, in patients with MIBC who were ineligible for or had refused cisplatin-based chemotherapy. 695 patients were randomized 1:1:1 to receive neoadjuvant durvalumab and EV followed by radical cystectomy and adjuvant durvalumab; neoadjuvant durvalumab, EV and tremelimumab followed by radical cystectomy and adjuvant durvalumab plus tremelimumab; or radical cystectomy alone. Dual primary endpoints were event-free survival (EFS) in the durvalumab-EV group and the durvalumab-EV-tremelimumab group, both compared with the control group. A key secondary endpoint was overall survival (OS), and safety was also assessed.2,3

In the doublet group, EFS and OS were both significantly improved compared with  the control group, with a 24-month EFS rate of 64% versus 45% (HR 0.51, 95% CI 0.38-0.67, P<0.0001) and OS of 78% versus 69% (HR 0.58, 95% CI 0.40-0.83, P=0.0027). In the triplet group, the 24-month EFS rate was significantly higher than in the control group, at 60% versus 45% in the control group (HR 0.61, 95% CI 0.47–0.80, P=0.0004), while OS showed no significant difference. 30% of patients in the doublet group and 42% in the triplet group experienced grade 3 or 4 treatment-related adverse events, with one treatment-related death reported.2,3

Thomas Powles, MBBS, MRCP, MD, Barts Cancer Centre, London, UK, comments on the impact of the results on clinical practice:

“Overall, when you look at the results of the VOLGA trial with that doublet, you can say this is a new option for patients in this environment. It’s a patient-friendly option, and it’s associated with great outcomes.”

These results demonstrate a EFS and OS benefit for durvalumab and EV over radical cystectomy alone, supporting the use of this combination as a potential new perioperative treatment for MIBC. Although the regimens were not directly compared in this trial, the addition of tremelimumab did not appear to provide any additional benefit; however, follow-up is ongoing.

References

  1. Cigliola A, Maiorano BA, Dengur D, et al. The Management of Muscle Invasive Bladder Cancer: State of the Art and Future Perspectives. Cancers. 2025 Dec;17(24):4017-4017.
  2. Powles T, Grande E, Simone G, et al. Durvalumab, Tremelimumab, and Enfortumab Vedotin in Muscle-Invasive Bladder Cancer. N Engl J Med. 2026 Oct.
  3. Powles T, 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. Abstract LBA2. Presented at the ESMO 2026 Congress; October 23-27, 2026; Madrid, Spain.