The FDA has approved durvalumab (Imfinzi) in combination with enfortumab vedotin-ejfv (Padcev) as neoadjuvant treatment, followed by single-agent adjuvant durvalumab after radical cystectomy, for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for or have refused cisplatin-based chemotherapy.¹

The November 13, 2026, decision is based on the phase 3 VOLGA trial (NCT04960709), in which the regimen reduced the risk of an event-free survival (EFS) event by 49% and the risk of death by 42% compared with radical cystectomy alone.^1,2 Grade 3 or higher adverse events (AEs) of any cause occurred in 71.1% of patients who received the doublet, compared with 50.2% of patients who underwent surgery alone.²

Under this regimen, enfortumab vedotin is given only in the neoadjuvant phase, for 3 cycles. The FDA approved the application 6 weeks ahead of its goal date under priority review and Project Orbis.¹

How was the VOLGA trial designed?

VOLGA was a randomized, open-label, multicenter, global phase 3 trial that enrolled 695 patients with clinical stage T2-T4aN0/1M0 or T1N1M0 MIBC who were candidates for radical cystectomy and were ineligible for or declined cisplatin-based chemotherapy.^2,3 Patients were randomly assigned 1:1:1 to 1 of 3 arms:

• Durvalumab plus enfortumab vedotin before surgery, followed by adjuvant durvalumab (n = 233)
• Durvalumab plus tremelimumab (Imjudo) and enfortumab vedotin before surgery, followed by adjuvant durvalumab plus 1 cycle of tremelimumab (n = 233)
• Radical cystectomy with or without approved adjuvant therapy (n = 229)^2,4

In the approved doublet regimen, patients weighing 30 kg or more receive durvalumab 1500 mg every 3 weeks plus enfortumab vedotin 1.25 mg/kg on days 1 and 8 of each 21-day cycle for 3 neoadjuvant cycles. After surgery, durvalumab 1500 mg is given every 4 weeks as a single agent for up to 9 cycles. Patients weighing less than 30 kg receive durvalumab at 20 mg/kg on the same schedules.¹

The dual primary end points were EFS for each experimental arm vs cystectomy alone; overall survival (OS) was the key secondary end point. Pathologic complete response (pCR), disease-free survival, and pathologic downstaging were also assessed.^2,5 The FDA based its review on EFS by blinded independent central review.¹

How much did durvalumab plus enfortumab vedotin improve survival?

At a prespecified interim analysis (data cutoff, March 2, 2026) with a median EFS follow-up of 22.9 months, the doublet was associated with the following outcomes vs cystectomy alone²:

• Median EFS: not reached (95% CI, 33.2 months-not reached) vs 12.1 months (95% CI, 7.6-27.0)¹
• EFS hazard ratio (HR): 0.51 (95% CI, 0.38-0.67; P < .001)
• 24-month EFS rate: 63.5% vs 45.1%
• OS HR: 0.58 (95% CI, 0.40-0.83; P = .003); median OS was not reached in either arm
• 24-month OS rate: 78.4% vs 69.4%
• pCR rate: 45.1% vs 9.6%

The triplet arm also showed a statistically significant improvement in EFS (HR, 0.61; 95% CI, 0.47-0.80; P < .001), with a 24-month EFS rate of 60.1%. However, the OS difference for the triplet was not statistically significant at the interim analysis (HR, 0.77; 95% CI, 0.54-1.07; P = .12), and follow-up is ongoing.² The triplet is not part of the approved indication.¹

Radical cystectomy was completed in 85.0% of patients in the doublet arm, 78.5% in the triplet arm, and 78.6% in the surgery-alone arm. Adjuvant treatment was completed by 54.9% of patients in the doublet arm.²

In an exploratory analysis presented at the European Society for Medical Oncology (ESMO) Congress 2026, 60% of patients in the doublet arm with detectable circulating tumor DNA (ctDNA) at baseline cleared it before cystectomy. The 24-month EFS rate was 81% among patients who achieved clearance vs 55% among those who remained ctDNA positive.³

What safety signals should nurses watch for with this regimen?

Treatment-related grade 3 or higher AEs occurred in 30.7% of patients in the doublet arm and 44.5% of patients in the triplet arm. One treatment-related death occurred in the doublet arm (multiple-organ dysfunction syndrome), compared with 5 in the triplet arm.²

According to data presented at ESMO, the most common any-grade AEs with the doublet were pruritus (44%), urinary tract infection (36%), and anemia (32%). Among enfortumab vedotin-associated treatment-related AEs, skin reactions occurred in 49% of patients, peripheral neuropathy in 18% (mostly grade 1), and hyperglycemia in 11%. Immune-mediated AEs of any grade occurred in 33% of patients in the doublet arm. AEs delayed surgery in 4% of patients who received the doublet.³

The FDA label includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. Adverse reactions and laboratory abnormalities reported in more than 20% of patients included increased aspartate aminotransferase and alanine aminotransferase, decreased hemoglobin, rash, pruritus, fatigue, diarrhea, nausea, peripheral neuropathy, and alopecia.¹

What did investigators say about the results?

Thomas Powles, MD, professor and chair of Barts Cancer Centre, Queen Mary University of London, and international coordinating investigator for VOLGA, described the need in this population when the topline results were announced.

"Up to half of patients with muscle-invasive bladder cancer are not eligible for cisplatin and face high rates of disease recurrence, even after having their bladder removed, leaving a significant need for new effective and well-tolerated treatments," Powles said in a news release.⁵

"The VOLGA results show that perioperative durvalumab significantly extends event-free survival and overall survival when combined with neoadjuvant enfortumab vedotin, with a manageable safety profile, compared to surgery for patients in this curative-intent setting," he added.⁵

How does this approval fit with other options for MIBC?

The approval adds a second perioperative enfortumab vedotin-based regimen for patients who cannot receive cisplatin. In July 2026, the FDA expanded the approval of pembrolizumab (Keytruda) with enfortumab vedotin as neoadjuvant and adjuvant treatment for all adults with MIBC who are candidates for surgery, regardless of cisplatin eligibility, as previously reported by Oncology Nursing News.⁷ That regimen was first approved for cisplatin-ineligible disease on the basis of the phase 3 KEYNOTE-905/EV-303 trial.⁸ Durvalumab is also approved with gemcitabine and cisplatin as perioperative treatment for cisplatin-eligible MIBC, based on the phase 3 NIAGARA trial.⁶

Key differences between the enfortumab vedotin-based regimens include the number of enfortumab vedotin cycles and whether it continues after surgery. In VOLGA, enfortumab vedotin was limited to 3 neoadjuvant cycles.¹

Limitations of VOLGA include its open-label design, the interim nature of the OS analysis, and a comparator arm that did not receive neoadjuvant systemic therapy. The trial was funded by AstraZeneca.²

What are the key takeaways for oncology nurses?

• Confirm eligibility: The indication covers adults with MIBC who are ineligible for or have refused cisplatin-based chemotherapy and who are planned for radical cystectomy.¹
• Teach the treatment timeline: Patients receive 3 neoadjuvant cycles of durvalumab every 3 weeks with enfortumab vedotin on days 1 and 8, then surgery, then up to 9 cycles of durvalumab every 4 weeks.¹
• Monitor skin, nerves, and glucose: Skin reactions (49%), peripheral neuropathy (18%), and hyperglycemia (11%) were reported as enfortumab vedotin-associated treatment-related AEs; early reporting can help keep patients on track for surgery.³
• Watch for immune-mediated AEs throughout: Immune-mediated AEs occurred in 33% of doublet-treated patients, and adjuvant durvalumab continues for months after cystectomy.^1,3
• Support adherence after surgery: Only 54.9% of patients completed adjuvant treatment, so postoperative follow-up and symptom management may help patients continue durvalumab.²
• Support shared decision-making: Patients and caregivers may be weighing this regimen against perioperative pembrolizumab plus enfortumab vedotin; schedule, cycle count, and toxicity profiles differ.^1,7

References

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

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

Powles T, Grande E, Simone G, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the phase 3 VOLGA trial. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA2.

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 May 2026. Accessed November 13, 2026. https://clinicaltrials.gov/study/NCT04960709

Perioperative Imfinzi plus neoadjuvant EV showed statistically significant and clinically meaningful improvements in event-free survival and overall survival in muscle-invasive bladder cancer in the Phase III VOLGA trial. News release. AstraZeneca. May 13, 2026. Accessed November 13, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/imfinzi-ev-improves-efs-os-in-bladder-cancer.html

Perioperative Imfinzi plus neoadjuvant enfortumab vedotin granted Priority Review in the US for patients with muscle-invasive bladder cancer. News release. AstraZeneca. September 25, 2026. Accessed November 13, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/perioperative-imfinzi-plus-neoadjuvant-enfortumab-vedotin-granted-priority-review-in-the-us-for-patients-with-muscle-invasive-bladder-cancer.html

ONN Staff. FDA expands pembrolizumab label for muscle-invasive bladder cancer. Oncology Nursing News. July 10, 2026. Accessed November 13, 2026. https://www.oncnursingnews.com/view/fda-expands-pembrolizumab-label-for-muscle-invasive-bladder-cancer

Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026;394(13):1257-1269. doi:10.1056/NEJMoa2511674