Clinical Summary: 

• Design/Population: The phase 3 VOLGA trial evaluated perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin versus radical cystectomy followed by observation or locally approved adjuvant treatment in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based therapy.
• Key Outcomes: Durvalumab plus enfortumab vedotin significantly improved event-free and overall survival compared with control, reducing the risk of an event-free survival event by 49% and death by 42%. The addition of tremelimumab also significantly improved event-free survival but did not demonstrate a statistically significant overall survival benefit at interim analysis.
• Clinical Relevance: These findings support perioperative durvalumab plus neoadjuvant enfortumab vedotin as a potential treatment strategy for patients with muscle-invasive bladder cancer who cannot receive or decline cisplatin-based therapy.

Results from the phase 3 VOLGA trial demonstrated that perioperative durvalumab plus neoadjuvant enfortumab vedotin significantly improved event-free and overall survival in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based therapy, supporting this combination as a potential perioperative treatment option.

These findings were presented by Thomas Powles, MD, MBBS, Barts Cancer Centre, London, United Kingdom, during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress.

In this open-label trial, researchers enrolled 695 patients with clinical stage T2 to T4aN0/1M0 or T1N1M0 disease who were either ineligible for or declined cisplatin-based treatment and scheduled to undergo radical cystectomy. Patients were randomized 1:1:1 to receive either durvalumab plus enfortumab vedotin (n = 233), durvalumab plus tremelimumab and enfortumab vedotin (n = 233), or radical cystectomy followed by observation or locally approved adjuvant treatment (n = 229). 

Patients in the experimental arms received 3 cycles of neoadjuvant enfortumab vedotin in combination with durvalumab, with or without tremelimumab, before undergoing radical cystectomy. The neoadjuvant regimen included 3 cycles of durvalumab and, in the triplet arm, 2 cycles of tremelimumab. Following surgery, patients received 9 cycles of adjuvant durvalumab, with 1 additional cycle of tremelimumab administered in the triplet arm. 

Dual primary end points included event-free survival (EFS) for durvalumab plus enfortumab vedotin versus control and EFS for durvalumab plus tremelimumab and enfortumab vedotin versus control. Key secondary end points included overall survival (OS) and safety.  

At a median follow-up of 22.9 months, durvalumab plus enfortumab vedotin significantly improved EFS compared with control, reducing the risk of an EFS event by 49% (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.38 to 0.67; P < .0001). The 24-month EFS rates were 64% and 45%, respectively. The 24-month OS rate was 78% in the durvalumab plus enfortumab vedotin arm and 69% in the control arm, reducing the risk of death by 42% (HR, 0.58; 95% CI, 0.40 to 0.83; P = .0027). 

In patients who received tremelimumab, the 24-month EFS rate was 60% in the durvalumab plus tremelimumab and enfortumab vedotin arm and 45% in the control arm (HR, 0.61; 95% CI, 0.47 to 0.80; P = .0004). The triplet regimen did not meet the threshold for statistical significance for OS at the interim analysis. Follow-up is ongoing to further characterize survival outcomes.

According to local review, pathological complete response was observed in 45% of patients in the durvalumab plus enfortumab vedotin arm and 10% of patients in the control arm. 

Radical cystectomy was completed in 85% of patients in the durvalumab plus enfortumab vedotin arm, 79% of patients in the triplet arm, and 78% of patients in the control arm. Following surgery, 55% of patients receiving durvalumab plus enfortumab vedotin and 42% receiving the triplet regimen completed adjuvant treatment.

Safety findings were consistent with the established profiles of the individual agents. Grade 3/4 treatment-related adverse events were reported in 30% of patients in the durvalumab plus enfortumab vedotin arm and 42% of patients in the durvalumab plus tremelimumab and enfortumab vedotin arm. 

Source: 

Powles TB, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: Results from the phase 3 VOLGA trial. Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. LBA2.