The Food and Drug Administration (FDA) has granted Priority Review to durvalumab plus neoadjuvant enfortumab vedotin for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or have declined cisplatin-based chemotherapy.

A Prescription Drug User Fee Act action is expected in the fourth quarter of 2026. Priority Review shortens the FDA’s review goal but does not change the evidentiary standard or amount to regulatory approval.

Dr. Jorge Garcia, chief of Solid Tumor Oncology at University Hospitals Seidman Cancer Center, describes the regulatory sequence as unusual.

“Physicians are being told that the application warrants expedited review before we have seen the actual hazard ratios, absolute EFS and OS differences, pathological response data, subgroup analyses, and complete safety results,” Dr. Garcia tells SurvivorNet Connect. 

“The Agency has access to the underlying clinical data submitted by the sponsor. Priority Review increases the interest in seeing the VOLGA results, but it should not substitute for seeing and critically evaluating the complete dataset,” he adds. 

VOLGA Tests Neoadjuvant EV Without Postoperative EV

The application was based on the results of  VOLGA, a global, randomized, open-label phase 3 trial that enrolled 695 radical-cystectomy candidates. Eligible patients had T2-T4aN0/1M0 or T1N1M0 urothelial carcinoma, an Eastern Cooperative Oncology Group performance status of 0 to 2, and no previous systemic chemotherapy or immunotherapy for muscle-invasive disease.

Patients were randomized equally to three groups. The doublet arm received three preoperative cycles of durvalumab plus enfortumab vedotin, followed by radical cystectomy and nine cycles of adjuvant durvalumab. A second experimental arm added two neoadjuvant doses and one postoperative dose of tremelimumab. The control arm underwent cystectomy with or without approved adjuvant treatment.

The sponsor describes event-free survival for each experimental comparison with control as the dual primary endpoints. Secondary outcomes include overall survival, pathological complete response, disease-free survival, and pathological downstaging.

At a planned interim analysis, durvalumab with neoadjuvant enfortumab vedotin reportedly produced statistically significant and clinically meaningful improvements in both event-free and overall survival. The triplet improved event-free survival, but its overall-survival result was not statistically significant and will be reassessed.

No numerical VOLGA efficacy results have been disclosed.

EV-Pembrolizumab Has Set a High Benchmark

VOLGA enters a setting reshaped by two positive phase 3 studies of perioperative enfortumab vedotin plus pembrolizumab.

In the predominantly cisplatin-ineligible KEYNOTE-905/EV-303 population, the pathological complete response rate was 57.1% with EV-pembrolizumab and 8.6% with surgery alone. Two-year event-free survival was 74.7% versus 39.4% (hazard ratio, 0.40), while two-year overall survival was 79.7% versus 63.1% (hazard ratio, 0.50).

KEYNOTE-B15/EV-304 compared EV-pembrolizumab with neoadjuvant gemcitabine-cisplatin in cisplatin-eligible patients. Pathological complete response rates were 55.8% and 32.5%, respectively. Two-year event-free survival was 79.4% versus 66.2% (hazard ratio, 0.53), and overall survival was 86.9% versus 81.3% (hazard ratio, 0.65).

Against that background, VOLGA is not establishing the general value of combining enfortumab vedotin with checkpoint blockade. Its design tests whether three preoperative EV cycles, followed by durvalumab alone, can support durable outcomes without postoperative EV.

“If VOLGA demonstrates a substantial and durable EFS and OS benefit with that strategy, it raises an important question: how much EV do our patients actually need?” Dr. Garcia notes. 

He cautions that VOLGA cannot establish that postoperative EV is unnecessary because it was not designed as a de-escalation comparison. Cross-trial comparisons also differ in eligibility, control treatment, checkpoint inhibitor, EV exposure, follow-up, and event definitions.

Safety and Sequencing Questions Remain

The sponsor reported that safety was consistent with the known profiles of durvalumab and enfortumab vedotin, with no new signals. Detailed rates of grade 3 or higher toxicity, treatment discontinuation, perioperative complications, neuropathy, skin toxicity, hyperglycemia, pneumonitis, and immune-mediated adverse events have not been presented.

Limiting EV to the neoadjuvant period could reduce cumulative peripheral neuropathy and postoperative treatment burden, but that remains an inference until exposure-adjusted safety and patient-reported outcomes are available.

VOLGA also cannot separate the contribution of neoadjuvant therapy from adjuvant durvalumab. Pathological response and postoperative circulating tumor DNA may eventually help identify patients who need escalation, continued immunotherapy, or surveillance alone. No validated biomarker currently determines those choices.

Until the complete dataset is presented, the filing supports regulatory interest in the regimen, not a definitive ranking among perioperative strategies.