Patients with muscle-invasive bladder cancer who received neoadjuvant and adjuvant durvalumab and neoadjuvant enfortumab vedotin with radical cystectomy, with or without peri- and postoperative tremelimumab, had significantly better event-free survival than those who underwent surgery alone.

Specifically, event-free survival at 24 months was 45.1% in the control group compared with 63.5% in the durvalumab + enfortumab vedotin group and 60.1% in the durvalumab–tremelimumab–enfortumab vedotin group, in the phase 3 open-label VOLGA trial. 

“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,” said lead author Thomas Powles, MBBS, MD, of Barts Cancer Institute at Queen Mary University of London, “We’re curing a lot of patients with bladder cancer for the first time with systemic therapy.”

Powles presented the results of the study at the European Society for Medical Oncology 2026, which published simultaneously in the New England Journal of Medicine. 

A ‘Massive’ Change in the Last 2 Years

Powles explained that only a couple of years ago, outcomes of people with muscle-invasive bladder cancer were “really dire,” with half of patients dying within 5 years of diagnosis, and 60% relapsing. The only treatment was cystectomy. 

Then, a 2024 study showed that the addition of perioperative durvalumab reduced death by 25%, and the drug was approved by the US Food and Drug Administration

(FDA) and the European Medicines Agency (EMA) for the treatment of muscle-invasive bladder cancer in 2025. 

And just last year, results from the KEYNOTE-905/EV-303 trial showed that adding enfortumab vedotin with pembrolizumab reduced risk of death by 40%–50%. Confirmation of those results in KEYNOTE-B15/EV-304 led to the drug combination being approved by the FDA earlier this year and by the EMA just this month.

“We’ve moved from patients with metastatic disease dying between 8 to 12 months to 3 years overall survival. We’ve moved these regimes into the perioperative space,” Powles said. 

The VOLGA Trial

The VOLGA trial looked at outcomes with shorter periods of systemic therapy with perioperative durvalumab, with and without the CTLA-4 inhibitor tremelimumab, plus neoadjuvant enfortumab vedotin. 

The trial enrolled 695 patients with muscle-invasive bladder cancer who were not eligible for (76%) or declined (24%) cisplatin-based chemotherapy. Patients were predominantly male (81%) with an average age of 72. More than half came from Europe, with approximately one fifth from Asia and one fifth from the Americas. Approximately half had high PD-L1 expression.

The trial had two intervention arms and a control arm. In the first intervention arm, 233 patients received neoadjuvant durvalumab with enfortumab vedotin every 3 weeks for three cycles and then underwent radical cystectomy, followed by adjuvant durvalumab every 4 weeks for nine cycles. In the other interventional arm, 233 patients received neoadjuvant durvalumab with enfortumab vedotin plus just two cycles of tremelimumab, followed by radical cystectomy and then adjuvant durvalumab with one cycle of tremelimumab. The control group of 229 patients received radical cystectomy without neoadjuvant or adjuvant medication. 

The primary endpoints were event-free survival in each interventional group with the secondary endpoints of overall survival. Compared with the control group, the risk of an event or death was reduced by 49% in patients receiving durvalumab plus enfortumab vedotin (hazard ratio [HR], 0.51; P < .001) and by 39% in those receiving the combination of durvalumab, tremelimumab, and enfortumab vedotin (HR, 0.61; P < .001).

Overall survival at 24 months was 78.4% in the durvalumab + enfortumab vedotin group, which was significantly higher than the 69.4% in the control group (HR, 0.58, P = .003). However, overall survival was not significantly different in the durvalumab–tremelimumab–enfortumab vedotin group (HR, 0.77, P = .12). 

In VOLGA, 87% of patients in the intervention arms completed the trial while only 79% in the control arm did.

More Adverse Events in Triplet Therapy Group

The safety profile generally followed what is expected from each of the drugs, Powles noted in his presentation. The group with tremelimumab had more immune-related adverse events (48%) than the intervention arm without it (33%), while the control arm had only 3%, Powles said.

Adverse events of grade 3 or higher occurred in half the control group (50.2%) compared to 71.1% of the durvalumab + enfortumab vedotin group and 79.5% in the durvalumab–tremelimumab–enfortumab vedotin group. Those deemed treatment-related included 30.7% in the doublet therapy group and 44.5% in the triplet therapy group. 

New Options

The VOLGA trial ”brings new options to this disease setting,” said invited discussant Michiel van der Heijden, MD, PhD, a medical oncologist at Netherlands Cancer Institute (NKI) in Amsterdam. 

There are similarities between the VOLGA trial and the KEYNOTE trials, said van der Heijden, including little difference in efficacy between durvalumab and pembrolizumab. One notable difference, however, was that enfortumab vedotin was not used in the adjuvant setting in VOLGA as it was in the KEYNOTE trials. 

“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.” 

As a result of the higher toxicity of tremelimumab, he called for more trials to explore which adjuvant components are best.

The research was funded by AstraZeneca. Powles reported grants, honoraria, and/or travel support from Astellas, AstraZeneca, Bristol Myers Squibb, Roche, Eisai, Exelixis, Ipsen, Incyte, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Seagen, Mashup Ltd, and Roche. 

Van der Heijden reported grants and/or consulting or advisory fees from AstraZeneca, BMS, Astellas, Pfizer/Seagen, Merck/MSD, Greywolf Therapeutics, Aktis Oncology, Janssen, Daiichi Sankyo, Roche, and 4SC. 

Tara Haelle has been an independent science/health journalist for over 15 years, with work appearing in over two dozen trade and consumer publications. She is author of Vaccination Investigation: The History and Science of Vaccines and The Informed Parent: A Science-Based Guide to the First Four Years. Tara is the Public Health Beat Leader for the Association of Health Care Journalists, where she develops resources to help other journalists report on medical studies and public health. She is based in Dallas, Texas.