Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: Results from the phase 3 VOLGA trial

doi:10.1056/nejmoa2608323

VOLGA

Patient / Population Intervention / Exposition Vergleich Endpunkt

In patients with muscle-invasive bladder cancer who were ineligible for or refused cisplatin, perioperative durvalumab plus neoadjuvant enfortumab vedotin improved event-free and overall survival compared with radical cystectomy followed by observation or locally approved adjuvant treatment.

N

—Patienten

Design

Phase 3, randomised, open-label trial (NCT04960709) in which patients with muscle-invasive bladder cancer (cT2-T4aN0/1M0 or cT1N1M0) who were ineligible for or refused cisplatin and were planned for radical cystectomy were randomised 1:1:1 to perioperative durvalumab plus neoadjuvant enfortumab vedotin (233), perioperative durvalumab plus tremelimumab plus neoadjuvant enfortumab vedotin (233) or control with radical cystectomy and observation or locally approved adjuvant treatment (229).

Endpunkt

Dual primary endpoints of event-free survival: durvalumab plus enfortumab vedotin vs control, and durvalumab plus tremelimumab plus enfortumab vedotin vs control. Overall survival was the key secondary endpoint.

ErgebnisEvent-free survival with durvalumab plus enfortumab vedotin vs control HR 0.51 (95% CI 0.38-0.67; P<0.0001), 24-month rate 64% vs 45%. With durvalumab plus tremelimumab plus enfortumab vedotin vs control HR 0.61 (95% CI 0.47-0.80; P=0.0004), 24-month rate 60% vs 45%. Overall survival with durvalumab plus enfortumab vedotin vs control HR 0.58 (95% CI 0.40-0.83; P=0.0027), 24-month rate 78% vs 69%. Durvalumab plus tremelimumab plus enfortumab vedotin did not meet significance for overall survival. Pathological complete response per local review 45% (95% CI 38.6-51.7) with durvalumab plus enfortumab vedotin vs 10% (95% CI 6.1-14.2) with control. Maximum grade 3/4 treatment-related adverse events occurred in 30% with durvalumab plus enfortumab vedotin and 42% with durvalumab plus tremelimumab plus enfortumab vedotin. Median event-free survival follow-up was 22.9 months.

Powles T, Grande E, Simone G, et al. N Engl J Med. 2026; published online 24 October. 10.1056/nejmoa2608323

Diskussion & Kritik

At a pre-planned interim analysis, both experimental arms met their event-free survival endpoints, and durvalumab plus enfortumab vedotin also improved overall survival, a hard endpoint, in patients who could not or would not receive cisplatin. Median follow-up was only 22.9 months, overall survival for the tremelimumab arm is still immature, and the trial was open label with a control arm whose adjuvant treatment varied by local practice. Adding tremelimumab brought more grade 3/4 treatment-related toxicity (42% vs 30%) and no reported survival advantage. Fewer patients completed adjuvant treatment in that arm (42% vs 55%). Pathological complete response was assessed by local review and not reported for the tremelimumab arm, the abstract gives no control-arm safety figures, ctDNA results are not yet shown, and the trial was funded by AstraZeneca.