Cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC) have long gone straight to cystectomy. The phase 3 VOLGA trial makes a strong case that they should no longer.

Three cycles of neoadjuvant durvalumab plus enfortumab vedotin (EV), followed by adjuvant durvalumab, cut the risk of an event-free survival (EFS) event by 49% and the risk of death by 42% versus cystectomy alone, with EV given only before surgery.

If the FDA approves the regimen, with a decision expected by the end of 2026, clinicians will have a second EV-based perioperative option alongside the already approved EV-pembrolizumab.

The two have not been compared head-to-head. Until then, patients who can’t receive cisplatin should be evaluated for EV-pembrolizumab or a clinical trial rather than surgery alone.

The interim results were presented at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid.

“In the past, we didn’t give anything before surgery, and this obviously establishes a new standard of care in this patient population that was unable to receive cisplatin-based therapy,” Dr. Joaquim Bellmunt, director of the Bladder Cancer Center at Dana-Farber Cancer Institute, tells SurvivorNet.

“Patients who were unfit for cisplatin chemotherapy or unfit for receiving neoadjuvant therapy, those patients were taken straight away to surgery,” he says.

Analyzing the Data

VOLGA enrolled patients with MIBC scheduled for radical cystectomy who were cisplatin-ineligible or declined cisplatin. Patients were randomized to one of three arms:

• Durvalumab plus enfortumab vedotin (233 people): This group got three rounds of both drugs before surgery, then nine rounds of durvalumab alone after surgery.
• Durvalumab plus tremelimumab plus enfortumab vedotin (233 people): This group got the same plan mentioned above, plus a third drug, tremelimumab (brand name Imjudo), which releases a different brake.
• Surgery (229 people): This group had surgery followed by observation, or another approved treatment after surgery if one was available where they lived.

The primary endpoint was EFS, defined as freedom from disease progression, recurrence, other major events, or death from any cause. OS and pathologic complete response (pCR) were also reported. Results come from a planned interim analysis at approximately two years of follow-up.

Dr. Bellmunt describes the rationale for the neoadjuvant approach: “Getting treatment before the surgery, what we are doing is we are cleaning the body of potential microscopic disease that we don’t even see.”

Halving the Risk of Recurrence and Cutting Deaths by 42%

Durvalumab + EV reduced the risk of an EFS event by 49% (HR, 0.51) and the risk of death by 42% (HR, 0.58) versus control. Median follow-up was 23 months for EFS and 26 months for OS.

• At two years, 64% of people in the durvalumab plus EV group were event-free, compared with 45% in the surgery group. The gap showed up early. At one year, it was 73% versus 50%.
• The combination also helped people live longer (overall survival). At two years, 78% of people in the durvalumab plus EV group were alive, compared with 69% in the surgery group.
• In 45% of people in the durvalumab plus EV group, doctors found no cancer at all in the bladder tissue removed during surgery. This is called a pathologic complete response. In the surgery group, it was 10%.

“When the pathology was assessed, there is no tumor — meaning that this combination wipes completely out the presence of tumor in the bladder,” Dr. Bellmunt says of patients who achieved pCR. More than half of patients in the doublet arm still had residual disease at cystectomy.

The triplet arm (durvalumab + tremelimumab + EV) also improved EFS versus control (HR, 0.61; 95% CI, 0.47–0.80; P = .0004), but the OS difference was not statistically significant at this interim analysis (HR, 0.77; 95% CI, 0.54–1.07; P = .1230). Follow-up is ongoing.

Three Cycles of EV, a Manageable Toxicity Profile

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 30% of patients receiving durvalumab + EV and 42% of those receiving the triplet. Serious AEs of any cause occurred in 63%, 70%, and 44% of the doublet, triplet, and control arms, respectively. The safety profile was consistent with the known profiles of each agent.

Among EV-associated TRAEs, skin reactions occurred in 49% of patients, peripheral neuropathy in 18%, and hyperglycemia in 11%.

In VOLGA, EV was limited to the neoadjuvant phase, unlike other perioperative EV regimens that continue it after surgery. “We are only giving three cycles before the surgery. We are not giving it [EV] after the surgery… likely with the shorter treatment, it is going to be better,” Dr. Bellmunt says. The two approaches have not been compared head to head.

Clinical Context

The FDA has granted priority review to durvalumab + EV for this indication, with a decision expected by the end of 2026. Perioperative EV plus pembrolizumab is already FDA-approved for MIBC, so clinicians may soon have two EV-based perioperative options for cisplatin-ineligible patients.

VOLGA complements NIAGARA, which added perioperative durvalumab to cisplatin-based neoadjuvant chemotherapy in cisplatin-eligible patients. “Based on the data from these trials [NIAGARA and VOLGA], we expect more patients are going to be cured; that’s the most important,” Dr. Bellmunt says.

The 45% pCR rate also raises the question of bladder preservation in selected complete responders, though VOLGA did not evaluate this. “If we see a complete pathological response, maybe there is no need to remove the bladder in all patients,” Dr. Bellmunt says.