November 2nd, 2026
Summary by Catlin Nalley
A perioperative treatment regimen combining durvalumab with enfortumab vedotin (EV) improved event-free survival (EFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or declined cisplatin-based chemotherapy, according to results from the phase III VOLGA trial highlighted at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid (Abstract LBA2). The findings were simultaneously published in The New England Journal of Medicine (2026; doi.org/10.1056/NEJMoa2608323).
“Patients with muscle-invasive bladder cancer require life-changing bladder removal surgery. Despite this, the cancer returns in about half of patients,” noted study author Thomas Powles, MD, Professor and Chair of Barts Cancer Centre at the Barts Health NHS Trust in London, UK, who presented the data at ESMO.
“A new regimen of perioperative durvalumab combined with enfortumab vedotin before surgery reduced the risk of death by 42%, with a manageable safety profile,” he said. “These practice-changing results support this approach as a patient centric, potential new standard of care in this setting.”
Trial Design & Methods
VOLGA (NCT04960709), a randomized, open-label, phase III trial, enrolled patients with MIBC (cT2–T4aN0/1M0 or cT1N1M0) who were ineligible for or refused cisplatin-based chemotherapy and were candidates for radical cystectomy.
Investigators randomized 695 patients to one of three arms: perioperative durvalumab plus neoadjuvant EV (233 patients); perioperative durvalumab and tremelimumab plus neoadjuvant EV (233 patients); or a control strategy consisting of radical cystectomy followed by observation or locally approved adjuvant treatment (229 patients).
In both experimental arms, patients received three cycles of neoadjuvant EV with durvalumab. In the triplet arm, tremelimumab was administered for two neoadjuvant cycles. Following radical cystectomy, patients received nine cycles of adjuvant durvalumab, with one additional cycle of tremelimumab in the triplet arm. The control arm consisted of radical cystectomy followed by observation or locally approved adjuvant treatment.
The dual primary endpoints were EFS for each experimental arm versus control. OS was the key secondary endpoint, with safety also evaluated. The analysis reported at ESMO had a data cutoff of March 2, 2026, and a median EFS follow-up of 22.9 months.
Key Findings
The durvalumab–EV doublet demonstrated significant improvements in both primary and key secondary efficacy outcomes. The EFS hazard ratio was 0.51 (95% CI: 0.38–0.67; P<0.0001), corresponding to a 49% reduction in the risk of an EFS event. At 24 months, estimated EFS was 64% with the combination versus 45% with control.
OS also favored the doublet, with a hazard ratio of 0.58 (95% CI: 0.40–0.83; P=0.0027). The estimated 24-month OS rate was 78% versus 69%, respectively. Median EFS had not yet been reached in the durvalumab–EV arm, compared with 12.1 months in the control arm. Median OS had not yet been reached in either arm at the time of analysis.
Pathological complete response (pCR), assessed by local review, occurred in 45% of patients receiving durvalumab–EV (95% CI, 38.6%–51.7%), compared with 10% in the control arm (95% CI, 6.1%–14.2%).
The triplet regimen also met its EFS endpoint, reducing the risk of an EFS event by 39% versus control (HR: 0.61; 95% CI: 0.47–0.80; P=.0004). The estimated 24-month EFS rate was 60%, compared with 45% in the control arm. However, the OS analysis did not reach statistical significance (HR: 0.77; 95% CI: 0.54–1.07), and follow-up remains ongoing.
Treatment delivery and tolerability are important considerations in this surgical population. Radical cystectomy was completed in 85% of patients assigned to durvalumab–EV, 79% assigned to the triplet, and 78% assigned to control. Among patients in the experimental arms, 55% in the doublet group and 42% in the triplet group completed adjuvant treatment. Grade 3 or 4 treatment-related adverse events occurred in 30% of patients receiving durvalumab–EV and 42% receiving the triplet.
Circulating tumor DNA (ctDNA) analyses also offered a potential avenue for further investigation. Using an ultrasensitive assay, investigators reported baseline ctDNA positivity in 78% of patients and clearance in 60% between baseline and the preoperative assessment.
Circulating tumor DNA (ctDNA) analyses provided additional exploratory findings. Using an ultrasensitive assay, investigators reported baseline ctDNA positivity in 78% of patients, with clearance in 60% of patients who had detectable ctDNA at baseline by the preoperative assessment. Patients whose ctDNA remained negative or cleared during treatment appeared to have more favorable outcomes than those with persistent ctDNA positivity, according to Powles and colleagues.
Clinical Implications
The VOLGA findings reinforce the expanding role of perioperative systemic therapy in MIBC and suggest that a shorter course of neoadjuvant EV combined with durvalumab, can deliver meaningful survival benefits for patients who are ineligible for or decline cisplatin-based chemotherapy.
“Perioperative durvalumab plus three neoadjuvant cycles of enfortumab vedotin shows a clinically meaningful and statistically significant improvement in event-free survival and overall survival,” Powles summarized during his ESMO presentation. He also emphasized the regimen’s tolerability, particularly during the adjuvant phase, while noting that follow-up of the tremelimumab-containing triplet remains ongoing.
Reflecting on the broader evolution of bladder cancer treatment, Powles emphasized the pace of progress in recent years, as advances in systemic therapy have moved beyond metastatic disease into the curative-intent setting. “We’re curing a lot of patients with bladder cancer for the first time with systemic therapy, and here we show that shorter periods of systemic therapy are associated with great outcomes,” he concluded.
Catlin Nalley is a contributing writer.