Unlocking Anti-Tumor Immunity with Durvalumab, Tremelimumab, and Enfortumab Vedotin

Perioperative durvalumab (Imfinzi; AstraZeneca) plus tremelimumab (Imjudo; AstraZeneca) followed by neoadjuvant enfortumab vedotin (EV, Padcev; Astellas Pharma US, Inc) led to significant and clinically relevant benefits in both event-free survival (EFS) and overall survival (OS). Data from the phase 3 VOLGA trial (NCT04960709) demonstrated that this regimen was superior to standard of care in patients with muscle invasive bladder cancer (MIBC).

Uncover the Combination

Bladder cancer ranks as the ninth most prevalent cancer globally, with over 614,000 new cases diagnosed annually. In 2024, about 117,500 patients received treatment for MIBC under the established standard of care—neoadjuvant cisplatin-based chemotherapy with radical cystectomy. A significant shift followed in 2025, when results from the NIAGARA phase 3 trial (NCT03732677) supported the addition of perioperative durvalumab to this regimen, redefining the treatment standard.¹

Despite this progress, the field faces persistent challenges: up to half of all MIBC patients are ineligible for cisplatin-based therapy, and roughly 50% of those who undergo radical cystectomy experience disease recurrence. The combination explored in the VOLGA trial presents patients with a treatment option with improved response rates and survival.¹

Durvalumab is a human monoclonal antibody that targets and binds PD-L1 to block its interaction with PD-1 and CD80—2 immune checkpoints responsible for inhibiting immune responses. By targeting PD-L1, durvalumab reactivates the antitumor response through restoration of the immune system's ability to recognize tumor cells.²

Tremelimumab is another human monoclonal antibody and targets CTLA-4, an immune checkpoint inhibitor that regulates T-cell activation; however, when overexpressed, the body’s immune activity is suppressed. By binding to CTLA-4, tremelimumab helps support immune-mediated cell death.²

Unlike durvalumab and tremelimumab, EV is an antibody drug conjugate targeting Nectin-4—a molecule responsible for cell adhesion. Research shows that overexpression of Nectin-4 may contribute to tumor cell growth and proliferation. By targeting this molecule, EV induces cell-cycle arrest and apoptosis.³

Together, these agents support 3 crucial mechanisms in fighting cancer: immune system activation, immune inhibition reversal, and direct malignant cell apoptosis.

The VOLGA Trial

VOLGA is a randomized, open-label, multicenter global, phase 3 trial investigating perioperative durvalumab with or without tremelimumab in combination with neoadjuvant EV as treatment for patients with MIBC undergoing radical cystectomy who are not eligible for or have declined cisplatin compared to radical cystectomy with or without approved adjuvant therapy.¹

The trial included 695 patients who were randomly assigned to 1 of 3 arms¹:

• Arm 1: 3 cycles of durvalumab and EV, plus 3 cycles of tremelimumab prior to surgery, followed by 9 cycles of durvalumab plus 1 cycle of tremelimumab as adjuvant therapy
• Arm 2: 3 cycles of durvalumab and EV prior to surgery, followed by 9 cycles of durvalumab adjuvant monotherapy
• Arm 3: the comparator arm consisting of cystectomy with or without approved adjuvant therapy

The trial has 2 primary end points. The first is EFS, measured from the point of randomization to the earliest occurrence of any of the following: disease recurrence after radical cystectomy, disease progression in patients who did not undergo radical cystectomy, failure to proceed to radical cystectomy due to residual disease, or death from any cause. EFS is assessed for both experimental arms against the comparator arm.¹

Secondary end points include OS—evaluated for arm 1 vs arm 3 and arm 2 vs arm 3—as well as pathologic complete response, disease-free survival, and pathologic downstaging, which were assessed across both experimental arms.¹

Findings

When added to neoadjuvant EV, perioperative durvalumab combined with tremelimumab delivered a statistically significant and clinically meaningful gain in EFS. A positive directional trend was also observed for OS, though this did not reach statistical significance at the prespecified interim analysis—formal OS results will be evaluated at a later timepoint.¹

From a safety standpoint, the regimen was well tolerated, with profiles that aligned with what had previously been established for each individual agent. No unexpected safety concerns emerged. Full results are expected to be presented at an upcoming medical congress and submitted to regulatory agencies worldwide.¹

“Up to half of patients with [MIBC] are not eligible for cisplatin and face high rates of disease recurrence, even after having their bladder removed, leaving a significant need for new effective and well-tolerated treatments,” Thomas Powles, MD, professor, chair of Barts Cancer Centre, London, UK, and international coordinating investigator for the trial, said in a news release.¹

“The VOLGA results show that perioperative durvalumab significantly extends [EFS] and [OS] when combined with neoadjuvant [EV], with a manageable safety profile, compared to surgery for patients in this curative-intent setting.”¹

REFERENCES

1. Perioperative Imfinzi plus neoadjuvant EV showed statistically significant and clinically meaningful improvements in event-free survival and overall survival in muscle-invasive bladder cancer in the Phase III VOLGA trial. AstraZeneca. May 14, 2026. Accessed May 20, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/imfinzi-ev-improves-efs-os-in-bladder-cancer.html

2. Positive VOLGA phase III results for Imfinzi plus neoadjuvant EV in MIBC. OncoDaily. May 15, 2026. Accessed May 20, 2026. https://oncodaily.com/oncolibrary/volga-phase-iii-results

3. Powles T, Rosenberg J, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. February 12, 2021. doi:10.1056/NEJMoa2035807