VOLGA phase 3: durvalumab with enfortumab vedotin raised 24-month survival in bladder cancer

Results of the phase 3 VOLGA trial, published in the New England Journal of Medicine, show that perioperative durvalumab combined with neoadjuvant enfortumab vedotin gave better survival than radical cystectomy alone in muscle-invasive bladder cancer. The trial enrolled 695 patients at 229 centers in 25 countries. All were ineligible for or declined cisplatin-based chemotherapy. nejm.orgNew England Journal of Medicinenejm.orgOpen source ↗

Trial design

Patients were randomized 1:1:1. The first group (233 patients) received durvalumab with enfortumab vedotin every 3 weeks for three cycles, then radical cystectomy, then adjuvant durvalumab every 4 weeks for nine cycles. The second group (233) received the same scheme with tremelimumab added: two cycles before surgery and one after. The control group (229) had cystectomy alone.

The dual primary end points were event-free survival in each durvalumab group compared with control. The two durvalumab groups were not compared with each other. The key secondary end point was overall survival. The trial was open-label.

Enfortumab vedotin is an antibody-drug conjugate that binds the protein nectin-4 on bladder cancer cells. Durvalumab blocks the PD-L1 protein. In this trial enfortumab vedotin was given only before surgery, and patients continued with immunotherapy afterwards.

Survival and safety

Estimated event-free survival at 24 months was 63.5% with durvalumab plus enfortumab vedotin and 45.1% with control (hazard ratio for an event or death 0.51; 95% CI 0.38 to 0.67; P<0.001). Estimated overall survival at 24 months was 78.4% versus 69.4% (hazard ratio for death 0.58; 95% CI 0.40 to 0.83; P=0.003). nejm.orgNew England Journal of Medicinenejm.orgOpen source ↗

In the three-drug group, estimated event-free survival at 24 months was 60.1% (hazard ratio vs. control 0.61; 95% CI 0.47 to 0.80; P<0.001). According to the study team's release, this group did not show a statistically significant overall survival improvement at this stage.

According to the same release, 45.1% of patients on the two-drug regimen had no detectable cancer in tissue examined after surgery, versus 9.6% with surgery alone.

Grade 3 or higher adverse events occurred in 71.1% of patients in the two-drug group (treatment-related, 30.7%), 79.5% in the three-drug group (treatment-related, 44.5%) and 50.2% in the control group. nejm.orgNew England Journal of Medicinenejm.orgOpen source ↗ The researchers reported no unexpected safety problems with the two-drug regimen and no increase in surgery-related complications.