Priority Review means the FDA intends to evaluate the application on an accelerated timeline, generally within six months. It does not mean the regimen has been approved, nor does it lower the evidence required for approval.

Treating Cancer Before and After Surgery

When bladder cancer is “muscle-invasive” that means it has grown into the bladder’s muscular wall. When it has not spread to distant organs, treatment often aims to cure the cancer through radical cystectomy, an operation that removes the bladder.

Surgery can remove visible disease, but microscopic cancer cells may already have escaped the bladder. These cells can later produce a metastatic recurrence.

“Cystectomy removes the cancer we can see, while systemic therapy is intended to eradicate microscopic disease that may already exist elsewhere and later cause metastatic recurrence,” Dr. Jorge A. Garcia, Division Chief of Solid Tumor Oncology at University Hospitals Seidman Cancer Center, tells SurvivorNet.

WATCH: Staging Muscle-Invasive Bladder Cancer: Understanding The Process

The proposed regimen begins with three cycles of durvalumab and enfortumab vedotin before surgery. Enfortumab vedotin is stopped after cystectomy, while durvalumab continues for nine postoperative cycles.

That design differs from other enfortumab vedotin combinations in which the drug is given both before and after surgery.

How The Treatment Combination Works

Enfortumab vedotin is an antibody-drug conjugate. It recognizes Nectin-4, a protein commonly found on bladder cancer cells, and delivers a cell-killing drug into those cells.

Durvalumab is an immunotherapy that blocks PD-L1, a protein cancer cells can use to suppress an immune response. Blocking PD-L1 can help immune cells recognize and attack the cancer.

The combination pairs direct cancer-cell killing with immune activation. It avoids cisplatin-based chemotherapy, but it can still produce substantial side effects.

The Data Behind The Priority Review

The drug application was based on results from the phase 3 VOLGA trial, which enrolled 695 patients who could not receive or declined cisplatin and were medically fit for radical cystectomy.

Patients were assigned to one of three groups: durvalumab with enfortumab vedotin, the same drugs with the additional immunotherapy tremelimumab, or surgery with or without an approved postoperative treatment.

Drugmaker AstraZeneca reported that durvalumab with enfortumab vedotin significantly improved event-free survival (EFS) and overall survival (OS) compared with the control strategy. Event-free survival measures how long patients remain alive without recurrence, progression, failure to undergo surgery when cancer remains, or another event defined by the study.

The company has not yet publicly released key data, though.

“The actual VOLGA hazard ratios, absolute EFS and OS differences, pathological response rates, subgroup analyses and detailed safety results have not yet been publicly presented,” Dr. Garcia notes.  “Until we see those data, we cannot responsibly compare the magnitude of benefit with EV/pembrolizumab.”

That comparison matters because enfortumab vedotin with pembrolizumab has already produced strong phase 3 results in this setting. In predominantly cisplatin-ineligible patients, the combination improved two-year event-free survival from 39.4% with surgery alone to 74.7%. It also increased the rate of complete disappearance of cancer at surgery from 8.6% to 57.1%.

VOLGA could provide another platinum-free option. Its distinctive feature may be the shorter exposure to enfortumab vedotin, which is not continued after surgery.

Side Effects Still Need to Be Defined

Enfortumab vedotin can cause serious skin reactions, peripheral neuropathy, high blood sugar, eye problems, and inflammation of the lungs.

Durvalumab can cause the immune system to attack healthy organs, including the lungs, intestines, liver, kidneys, thyroid, adrenal glands, and skin.

AstraZeneca reported no new safety signals in VOLGA, but that statement cannot replace the complete safety dataset. Patients will need to understand how frequently serious side effects occurred, whether treatment delayed surgery, and how often either drug had to be interrupted or stopped.

Questions To Ask Your Doctor

• Am I eligible for cisplatin, and why might I choose a non-cisplatin treatment?
• Is durvalumab with enfortumab vedotin currently approved for my situation?
• What treatments are available to me now while the FDA reviews this application?
• Could treatment before surgery delay or affect my radical cystectomy?
• How would this strategy compare with enfortumab vedotin plus pembrolizumab?

Learn more about SurvivorNet's rigorous medical review process.

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