Durvalumab Plus Enfortumab Vedotin Improves Survival in Cisplatin-Ineligible MIBC

Perioperative durvalumab (Imfinzi) plus neoadjuvant enfortumab vedotin-ejfv (Padcev) improved event-free survival (EFS) and overall survival (OS) vs upfront radical cystectomy in patients with muscle-invasive bladder cancer (MIBC) who could not receive or declined cisplatin-based chemotherapy, according to findings from the phase 3 VOLGA trial (NCT04960709) presented at the 2026 ESMO Congress.¹

At a median follow-up of 23 months, median EFS was not reached (NR; 95% CI, 33.2-not calculated [NC]) with durvalumab plus enfortumab vedotin (n = 233) vs 12.1 months (95% CI, 7.6-27.0) in the control arm (n = 229; HR, 0.51; 95% CI, 0.38-0.67; P < .0001). Moreover, the 12- and 24-month EFS rates were 73% and 64% vs 50% and 45% for each arm, respectively. At a median follow-up of 26 months, median OS was NR (95% CI, NC-NC) in the durvalumab arm vs NR (95% CI, 37.7-NC) in the control arm (HR, 0.58; 95% CI, 0.40-0.83; P = .0027), with 12- and 24-month OS rates of 87% and 78% compared with 81% and 69% for each of the respective arms.

The triplet of durvalumab, tremelimumab-actl (Imjudo), and enfortumab vedotin (n = 233) also improved EFS vs control, the trial’s other dual primary end point with the median EFS being NR (95% CI, 27.9-NC) for the triplet arm and 12.1 months (95% CI, 7.6-27) for the control arm (HR, 0.61; 95% CI, 0.47-0.80; P = .0004).

Respective 12- and 24-month EFS rates were 67% and 60% compared with 50% and 45%. The OS difference with the triplet was not statistically significant at the interim analysis (HR, 0.77; 95% CI, 0.54-1.07; P = .1230).

“We've cured a lot of patients with bladder cancer for the first time with systemic therapy, and here we show that short and periodic systemic therapy are associated with great outcomes,” said presenting author Thomas Powles, MBBS, MD, of Barts Cancer Institute, Queen Mary University of London, in the United Kingdom.

How was the VOLGA trial evaluating durvalumab and enfortumab vedotin in MIBC designed?

The global, randomized trial enrolled patients who were at least 18 years old with MIBC that could not receive or declined cisplatin.^1,2 Patients could also have urothelial carcinoma or urothelial carcinoma with divergent differentiation or histological subtypes.

In the doublet arm, patients received 3 cycles of neoadjuvant durvalumab at 1500 mg plus enfortumab vedotin at 1.25 mg/kg every 3 weeks, followed by radical cystectomy and 9 cycles of adjuvant durvalumab every 4 weeks. The triplet arm added tremelimumab at 75 mg every 3 weeks for 2 neoadjuvant cycles and 1 adjuvant cycle every 4 weeks. The control arm went straight to radical cystectomy, with observation or locally approved therapy afterward.

Each experimental arm was compared with control on the dual primary end point of EFS, as assessed by blinded independent central review. OS served as the key secondary end point, and additional secondary end points included pathologic complete response (pCR) and quality of life measured with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

Baseline characteristics revealed that respective median ages in the doublet, triplet, and control arms were 72 years (range, 31-87), 71 years (range, 30-87), and 72 years (range, 38-87), and most patients were male (doublet, 82%; triplet, 79%; control, 82%).¹ Most patients were enrolled in Europe (60%; 52%; 56%), and an ECOG performance status of 0 was reported in 67%, 62%, and 66% of patients, respectively. Current nicotine use was reported in 24%, 17%, and 14% of patients, and high tumor PD-L1 expression was observed in 52% of patients in each arm. Tumor stage was T2N0M0 in 35%, 37%, and 36% of patients; T3-4aN0M0 in 48% of each arm; and T1-4aN1M0 in 16%, 14%, and 15%. Overall, 75%, 76%, and 77% of patients were ineligible for cisplatin.

Did durvalumab plus enfortumab vedotin improve pCR and circulating tumor DNA clearance in MIBC?

The EFS benefit with durvalumab plus enfortumab vedotin held across the subgroups analyzed, including patients with high (HR, 0.58; 95% CI, 0.39-0.86) and low or negative (HR, 0.46; 95% CI, 0.31-0.67) PD-L1 expression, in addition to those who were cisplatin ineligible (HR, 0.53; 95% CI, 0.38-0.72) or refused (HR, 0.49; 95% CI, 0.26-0.91).

By local pathology review, the pCR rate was 45% (95% CI, 38.6%-51.7%) with the doublet vs 10% (95% CI, 6.1%-14.2%) with control (risk ratio, 4.7; 95% CI, 3.1-7.3). By central independent review, these respective rates were 40% (95% CI, 34.0%-47.0%) vs 8% (95% CI, 5.1%-12.7%), respectively (risk ratio, 4.8; 95% CI, 3.1-7.9).

In a circulating tumor DNA (ctDNA) analysis of patients in the doublet arm with matched evaluable samples (n = 112), 78% were ctDNA positive at baseline (n = 87), and 60% of these patients cleared ctDNA before radical cystectomy. The 24-month EFS rates were 91% for patients who were persistently ctDNA negative, 81% for those who achieved clearance, and 55% for those who remained ctDNA positive.

What was the safety profile of durvalumab plus enfortumab vedotin in VOLGA?

In the safety population, grade 3 or 4 adverse effects (AEs) of any cause occurred in 64% of patients treated with the doublet (n = 228), 70% of those who received the triplet (n = 229), and 44% of those in the control arm (n = 229). Serious AEs occurred in 63%, 70%, and 44% of patients, respectively, and AEs led to death in 7%, 9%, and 6%. Treatment-related AEs (TRAEs) of grade 3 or 4 occurred in 30% of the doublet arm and 42% of the triplet arm, and TRAEs led to death in 1 patient and 5 patients, respectively.

Immune-mediated AEs occurred in 33%, 48%, and 3% of patients in the doublet, triplet, and control arms, respectively. In the doublet arm, AEs led to discontinuation of any study treatment in 21% of patients and to surgery delay in 4%.

The most common AEs with the doublet were pruritus (44%), urinary tract infection (36%), and anemia (32%). Among TRAEs associated with enfortumab vedotin, skin reactions occurred in 49% of patients, peripheral neuropathy in 18%, and hyperglycemia in 11%.

References

1. Powles T. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Paper presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain
2. Treatment combination of durvalumab, tremelimumab and enfortumab vedotin or durvalumab and enfortumab vedotin in patients with muscle invasive bladder cancer ineligible to cisplatin or who refuse cisplatin (VOLGA). ClinicalTrials.gov. Updated June 4, 2026. Accessed October 24, 2026. https://clinicaltrials.gov/study/NCT04960709?id=NCT04960709&viewType=Card&rank=1