FDA Approves Perioperative Durvalumab Plus Enfortumab Vedotin-ejfv for MIBC

The FDA approved durvalumab (Imfinzi; AstraZeneca) in combination with enfortumab vedotin-ejfv (EV) as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after radical cystectomy, for adult patients with MIBC who are ineligible for or have refused cisplatin-based chemotherapy.

According to the FDA, the application received priority review and was approved 6 weeks ahead of its Prescription Drug User Fee Act date.¹ The approval is supported by data from the global, phase 3 VOLGA trial (NCT04960709)², published October 24, 2026, in The New England Journal of Medicine.³

Patients with MIBC who cannot receive or decline cisplatin-based chemotherapy have historically had suboptimal outcomes. The phase 3 KEYNOTE-905/EV-303 trial (NCT03924895) established perioperative EV, a nectin-4–directed antibody-drug conjugate, plus pembrolizumab (Keytruda; Merck) as an option for this population, with EV given for 3 cycles before and 6 cycles after cystectomy. However, the optimal timing and duration of EV, including whether postoperative treatment is necessary, has remained uncertain.^2,3

The durvalumab regimen evaluated in VOLGA takes a different approach, concentrating EV before surgery while delivering immunotherapy both before and after cystectomy. Investigators noted that this design limits postoperative treatment burden, which can be difficult for patients after major surgery.^2,3

Trial Design and Results

VOLGA was an open-label, randomized trial conducted at 229 sites in 25 countries. A total of 695 patients with MIBC (clinical stage T2–T4aN0–1M0) or urothelial carcinoma of the bladder (clinical stage T1N1M0) who were fit for cystectomy were randomly assigned 1:1:1 to neoadjuvant durvalumab plus EV, followed by cystectomy and adjuvant durvalumab (n = 233); neoadjuvant durvalumab, tremelimumab, and EV, followed by cystectomy and adjuvant durvalumab plus tremelimumab (n = 233); or radical cystectomy alone (n = 229).^2,3

Cisplatin ineligibility was defined by at least 1 Galsky criterion; patients with ongoing grade 2 or higher neuropathy were excluded. Overall, 76.1% of patients were cisplatin ineligible, most commonly because of creatinine clearance below 60 mL/min, and 23.9% declined cisplatin.

The median patient age was about 72 years. Dual primary end points were event-free survival (EFS), assessed by blinded independent central review, for each durvalumab arm vs control. Overall survival (OS) was the key secondary end point.²

At a median follow-up of about 22.9 months, durvalumab plus EV significantly improved EFS compared with cystectomy alone (HR, 0.51; 95% CI, 0.38-0.67; P < .001).³ Median EFS was not reached in the combination arm vs 12.1 months in the control arm.¹ Estimated 24-month EFS was 63.5% vs 45.1%, respectively. The regimen also significantly improved OS (HR, 0.58; 95% CI, 0.40-0.83; P = .003), with estimated 24-month OS of 78.4% vs 69.4%. Median OS was not reached in either arm.^1,3

In the intention-to-treat population, the pathologic complete response rate by local review was approximately 45.1% with the combination vs 9.6% with cystectomy alone. Among patients in the combination arm who underwent cystectomy, the rate was 53.0%. The triplet regimen including tremelimumab also improved EFS vs control (HR, 0.61; 95% CI, 0.47-0.80; P < .001), but, according to the investigators, the OS difference was not considered statistically significant (HR, 0.77; 95% CI, 0.54-1.07; P = .12). The triplet was associated with more treatment-related adverse events (AEs).³

Safety and Dosing

Grade 3 or higher AEs of any cause occurred in approximately 71.1% of patients in the durvalumab plus EV arm (treatment related, 30.7%) and in 50.2% of the control arm. The most common AEs in the combination arm were pruritus (43.9%), urinary tract infection (36.4%), anemia (32.0%), diarrhea (26.3%), constipation (24.6%), decreased appetite (24.1%), and rash (22.4%).³

Skin reactions occurred in 48.7% of patients (grade 3, 4.4%; grade 4, 0.4%), and treatment-related peripheral neuropathy occurred in 17.5%, nearly all grade 1 or 2. Immune-mediated AEs occurred in approximately 32.9% of patients. AEs that led to discontinuation of any treatment occurred in approximately 21.1% of patients, and treatment-related death only occurred in 0.4% (n = 1).³

Notably, the combination did not compromise surgery. Cystectomy was performed in 85.0% of patients in the combination arm vs 78.6% of the control arm, and surgery-related AEs within 90 days occurred in 60.1% vs 67.6%, respectively. Health-related quality of life was maintained during treatment.³

The durvalumab label includes warnings for immune-mediated AEs, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.¹

Dosing

For patients who weigh at least 30 kg, the FDA-recommended regimen is durvalumab 1500 mg every 3 weeks plus EV 1.25 mg/kg on days 1 and 8 of each 21-day cycle for 3 cycles before surgery, followed by durvalumab 1500 mg every 4 weeks for up to 9 cycles after surgery.

For patients who weigh less than 30 kg, weight-based durvalumab dosing at 20 mg/kg on the same schedules are recommended. Treatment continues until disease progression that precludes surgery, recurrence, unacceptable toxicity, or completion of 9 adjuvant cycles.¹

Implications for Pharmacists

The approval gives cisplatin-ineligible patients a perioperative option that limits EV exposure to the neoadjuvant phase. Pharmacists can support patients by counseling on skin reactions and pruritus, monitoring for peripheral neuropathy and hyperglycemia, and screening for immune-mediated AEs such as hypothyroidism throughout the adjuvant phase.³ Coordinating timing between the final neoadjuvant dose and surgery is also important, as the median interval in VOLGA was 42 days.³

The investigators emphasized that the open-label design may have influenced treatment decisions, and that approximately 21.4% of control patients did not undergo planned cystectomy. The VOLGA trial is ongoing, and longer follow-up will further characterize survival outcomes.³

REFERENCES

1. FDA approves durvalumab with enfortumab vedotin-ejfv for muscle-invasive bladder cancer. News release. FDA. November 13, 2026. Accessed November 13, 2026. https://www.fda.gov/drugs/cancer-approvals/fda-approves-durvalumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer

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 identifier: NCT04960709. Updated June 4, 2026. Accessed November 13, 2026. https://clinicaltrials.gov/study/NCT04960709

3. Powles T, Grande E, Simone G, et al; VOLGA Investigators. Durvalumab, tremelimumab, and enfortumab vedotin in muscle-invasive bladder cancer. N Engl J Med. Published online October 24, 2026. doi:10.1056/NEJMoa2608323