Design: Phase 3, open-label, three-arm randomised trial (VOLGA)
Population: 695 patients with muscle-invasive bladder cancer ineligible for or declining cisplatin
Primary outcome: Event-free survival for each durvalumab arm vs cystectomy alone
Effect: 2-year EFS 63.5% vs 45.1% (HR 0.51); 2-year OS 78.4% vs 69.4% (HR 0.58)

VOLGA was a phase 3 open-label trial in 695 patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin chemotherapy — a group for whom the standard has been cystectomy alone. Patients were randomised to three cycles of neoadjuvant durvalumab with enfortumab vedotin, then cystectomy and adjuvant durvalumab; the same with tremelimumab added; or cystectomy alone.

Two-year event-free survival was 63.5% with durvalumab–enfortumab vedotin against 45.1% with surgery alone (HR 0.51, 95% CI 0.38 to 0.67), and overall survival 78.4% against 69.4% (HR 0.58, 0.40 to 0.83). Adding tremelimumab gave event-free survival of 60.1% (HR 0.61) with more toxicity; the two durvalumab groups were not compared directly. Grade 3 or worse adverse events of any cause occurred in 71.1% with durvalumab–enfortumab vedotin against 50.2% with surgery alone.

For a population often too frail or with too little kidney function for cisplatin, this offers the first perioperative regimen to improve overall survival over surgery alone. The toxicity is real, and enfortumab vedotin's skin, neuropathy and glucose effects need monitoring. Availability and cost will shape uptake in India.

Refer cisplatin-ineligible patients with muscle-invasive bladder cancer for discussion of perioperative therapy before cystectomy.
Durvalumab with enfortumab vedotin improved two-year overall survival from 69.4% to 78.4%.
Expect more grade 3 or worse toxicity than with surgery alone; plan for it.
Monitor for skin reactions, neuropathy and hyperglycaemia with enfortumab vedotin.
Adding tremelimumab added toxicity without a demonstrated extra benefit.

Why it matters

Patients who cannot have cisplatin have had only surgery to offer, and now have a regimen with an overall survival gain.

The statistics, in plain English

An overall survival hazard ratio of 0.58 means about 42% lower risk of death over the follow-up. At two years that was about nine more patients alive per 100 treated.