In the VOLGA trial, perioperative durvalumab plus enfortumab vedotin, with or without tremelimumab, was tested against surgery alone in muscle-invasive bladder cancer patients ineligible for cisplatin-based chemotherapy.

The study targets patients unable or unwilling to receive platinum-based chemotherapy, signaling a shift toward immunotherapy–antibody–drug conjugate combinations as alternatives to traditional chemotherapy.

The phase III VOLGA results show the combination therapy significantly reduced recurrence by 49% and mortality by 42% in this hard-to-treat population.

Findings were presented at ESMO 2026 and published in NEJM, with funding from AstraZeneca and disclosures from investigators.

Adverse events were higher with tremelimumab: immune-related events occurred in 48% vs 33% without tremelimumab and 3% in control; grade 3+ events rose to 50.2% (control), 71.1% (doublet), and 79.5% (triplet).

More than three-quarters of patients on the regimen survived to two years with preserved quality of life, suggesting a potential new standard for this population.

The report notes that hematuria is a common early warning sign of bladder cancer, underscoring the need for prompt evaluation and timely treatment.

At 24 months, event-free survival was 45.1% in control, 63.5% with durvalumab plus enfortumab vedotin, and 60.1% with the triplet regimen.

Compared with control, durvalumab plus enfortumab vedotin reduced the risk of an event or death by 49% (HR 0.51), while the triplet regimen reduced risk by 39% (HR 0.61).

Overall survival at 24 months was 78.4% for durvalumab plus enfortumab vedotin versus 69.4% in control; the triplet did not show a statistically significant OS difference.

Italian AIOM experts and participating centers view the approach as potentially raising cure rates and lowering recurrence, marking a major advance in perioperative bladder cancer therapy.

The trial enrolled 695 patients (median age ~72; 81% male), with broad geographic representation, and about half had high PD-L1 expression.