Patients with muscle-invasive bladder cancer who received neoadjuvant and adjuvant durvalumab and neoadjuvant enfortumab vedotin achieved an event-free survival rate of 63.5% at 24 months, significantly outperforming the 45.1% rate seen in surgery-alone controls during the phase 3 VOLGA trial presented at the European Society for Medical Oncology 2026.
Durvalumab Combined with Enfortumab Vedotin Reduces Risk of Death
- The VOLGA trial demonstrated a 49% reduction in the risk of an event or death for patients receiving durvalumab combined with enfortumab vedotin (hazard ratio, 0.51; P < .001).
- Overall survival at 24 months reached 78.4% in the doublet intervention group, compared with 69.4% in the control group.
- Safety data indicated grade 3 or higher adverse events in 71.1% of the doublet group and 79.5% of the triplet group containing tremelimumab, versus 50.2% in controls.
VOLGA Trial Evaluates Perioperative Therapy for Bladder Cancer
The open-label VOLGA trial enrolled 695 patients with muscle-invasive bladder cancer who were either ineligible for or declined cisplatin-based chemotherapy. Led by Thomas Powles, MBBS, MD, of Barts Cancer Institute at Queen Mary University of London, the study evaluated shorter periods of systemic therapy using perioperative durvalumab, with and without the CTLA-4 inhibitor tremelimumab, alongside neoadjuvant enfortumab vedotin.
Patients were randomized into two intervention arms and a control arm. A total of 233 patients received neoadjuvant durvalumab with enfortumab vedotin every 3 weeks for three cycles before radical cystectomy, followed by adjuvant durvalumab every 4 weeks for nine cycles. Another 233 patients received the same regimen plus two cycles of tremelimumab neoadjuvantly and one cycle adjuvantly. The control group of 229 patients underwent radical cystectomy without perioperative medication.
Event-free survival at 24 months reached 63.5% in the durvalumab plus enfortumab vedotin group and 60.1% in the durvalumab-tremelimumab-enfortumab vedotin group, compared to 45.1% in the control arm. The risk of an event or death fell by 49% in the doublet arm (hazard ratio [HR], 0.51; P < .001) and by 39% in the triplet arm (HR, 0.61; P < .001), as detailed in data published simultaneously in the New England Journal of Medicine.
| Treatment Arm | 24-Month Event-Free Survival | Hazard Ratio (vs. Control) | 24-Month Overall Survival |
|---|---|---|---|
| Control (Surgery Only) | 45.1% | Reference | 69.4% |
| Durvalumab + Enfortumab Vedotin | 63.5% | 0.51 (P < .001) | 78.4% |
| Durvalumab + Tremelimumab + Enfortumab Vedotin | 60.1% | 0.61 (P < .001) | Not significantly different (HR, 0.77) |
Evolving Standards in Perioperative Care
Treatments for muscle-invasive bladder cancer have changed rapidly over a two-year window. Historically, outcomes remained poor, with half of patients dying within 5 years of diagnosis and 60% experiencing relapse following cystectomy alone.
Cisplatin-ineligible bladder cancer, VOLGA (ESMO 2026, NEJM): 3 cycles of enfortumab vedotin + durvalumab before cystectomy. 2-year survival 78% vs 69% with surgery straight away.The surgeon's fear with drugs-first is losing patients before theatre. 85% still reached cystectomy… pic.twitter.com/QOgBSKldob
Progress began when a 2024 trial demonstrated that adding perioperative durvalumab reduced death by 25%. That data supported approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2025. Subsequently, the KEYNOTE-905/EV-303 trial showed that adding enfortumab vedotin with pembrolizumab reduced the risk of death by 40% to 50%. Confirmation from KEYNOTE-B15/EV-304 secured FDA approval earlier this year and EMA clearance just this month.
I think it’s fair to say we’ve been on a long journey in the last 5 years with 25 randomized phase 3 studies in bladder cancer,
Powles noted during his presentation at the European Society for Medical Oncology meeting. We’re curing a lot of patients with bladder cancer for the first time with systemic therapy.
🚨⭐ #ESMO26 | GU ONCOLOGY — DAY 2 HIGHLIGHTSA major day for bladder and prostate cancer: practice-relevant phase III data, longer survival follow-up and new molecular clues.🟠 VOLGA | LBA2 — A pivotal MIBC resultIn cisplatin-ineligible/refusing MIBC, perioperative… pic.twitter.com/qN937Dgtx8
Tremelimumab Increases Immune-Related Adverse Events
Adding the CTLA-4 inhibitor tremelimumab to the regimen increased immune-related adverse events. The triplet arm recorded immune-related toxicities in 48% of patients, compared with 33% in the doublet arm without tremelimumab, and 3% in the control group.
Adverse events of grade 3 or higher affected 79.5% of the triplet group and 71.1% of the doublet group, versus 50.2% among surgery-only controls. Treatment-related severe events occurred in 44.5% of the triplet therapy arm and 30.7% of the doublet therapy arm.
🌊 VOLGA | ESMO 2026A River by Name. A New Course in Bladder Cancer Treatment?Named after the Volga River — Europe's longest river, flowing through Russia into the Caspian Sea.Cisplatin-Free. Adjuvant EV-Free.The Phase III VOLGA trial (N = 695) evaluated perioperative… pic.twitter.com/kPHAb1NmjC
Invited discussant Michiel van der Heijden, MD, PhD, a medical oncologist at the Netherlands Cancer Institute in Amsterdam, pointed out distinctions between VOLGA and the KEYNOTE trials. Unlike the KEYNOTE protocols, VOLGA did not use enfortumab vedotin in the adjuvant setting.
The use of a cytotoxic agent in the adjuvant setting is new, and patients can struggle to receive this therapy after their major surgery,
van der Heijden said. The VOLGA trial shows that it is possible to have a positive result without using enfortumab vedotin in the adjuvant setting, and certainly more trials are needed to define which adjuvant components are really needed.
He also advocated for further studies to clarify the optimal role for adjuvant tremelimumab given its higher toxicity profile.
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