A Cisplatin-Free Perioperative Option for MIBC
- The VOLGA trial is testing a solution to a major unmet need: a perioperative option for patients with muscle-invasive bladder cancer who cannot receive or decline cisplatin.
- In topline results from the phase 3 trial, perioperative durvalumab plus neoadjuvant enfortumab vedotin led to statistically significant and clinically meaningful improvements in both event-free survival and overall survival compared with radical cystectomy with or without approved adjuvant therapy.
- The trial could reshape pre-surgery treatment discussions by offering a cisplatin-free perioperative option before cystectomy pending full dataset.
The positive results from the VOLGA trial could become one of the most clinically relevant bladder cancer stories from ASCO 2026. The research focused on a group of patients who need curative-intent treatment but often cannot receive the classic cisplatin-based pathway.
In topline results from the phase 3 trial, AstraZeneca reported that perioperative durvalumab plus neoadjuvant enfortumab vedotin led to statistically significant and clinically meaningful improvements in both event-free survival and overall survival compared with radical cystectomy with or without approved adjuvant therapy. The trial enrolled patients with muscle-invasive bladder cancer who were ineligible for cisplatin or who declined cisplatin-based chemotherapy.
That population is important because cisplatin ineligibility is common in bladder cancer.
“In the bladder cancer space for decades, patients that were cisplatin-ineligible were sort of neglected because they were just going for surgery,” Dr. Alexandra Drakaki, a GU medical oncologist at UCLA Health, tells SurvivorNet Connect. “They wouldn’t have good treatments that were safe and effective.”
Many patients have kidney dysfunction, hearing loss, neuropathy, frailty, or other medical issues that make cisplatin unsafe or impractical. For years, these patients often moved directly to surgery without the same level of evidence-based systemic therapy available to cisplatin-eligible patients.
What Did VOLGA Show?
VOLGA is a randomized, open-label, global phase 3 trial of patients with muscle-invasive bladder cancer undergoing radical cystectomy. The study tested two perioperative strategies: durvalumab plus enfortumab vedotin, with or without tremelimumab, compared with radical cystectomy with or without approved adjuvant therapy.
- Durvalumab targets PD-L1.
- Tremelimumab targets CTLA-4.
- Enfortumab vedotin is an antibody-drug conjugate directed against Nectin-4, a target commonly expressed in urothelial cancer.
The rationale comes partly from the success of enfortumab vedotin plus immunotherapy in advanced bladder cancer. EV-302 showed that enfortumab vedotin plus pembrolizumab improved outcomes in the metastatic setting, changing expectations for what an antibody-drug conjugate plus checkpoint inhibitor can do in urothelial cancer.
“So we really know that from the EV-302 study that EV along with immune checkpoint inhibitor and pembro in that setting improved survival, prolonged event-free survival,” Dr. Drakaki explains. “Knowing that this regimen is so effective in the metastatic setting, it makes perfect sense to study in the early time of diagnosis. So can we actually cure people early on?”
That question is central to VOLGA. The trial is not simply asking whether another immunotherapy combination works. It is asking whether a cisplatin-free perioperative approach can reduce disease burden before surgery, help patients get safely through cystectomy, and lower the chance that bladder cancer comes back afterward.
“When we see patients with muscle-invasive disease, we always try to think how can we decrease disease burden?” Dr. Drakaki adds. “How can we safely get them through surgery and decrease the risk of recurrence?”
Treatment-Selection Questions Remain
The study also raises an important treatment-selection question. In the topline analysis, the durvalumab plus enfortumab vedotin arm improved both event-free survival and overall survival.
The tremelimumab-containing arm also improved event-free survival, but overall survival showed only a favorable trend that was not statistically significant at the interim analysis. That distinction matters clinically, because adding CTLA-4 blockade may increase immune-related toxicity, and physicians will need to understand whether the added intensity provides enough benefit for the right patients.
Another notable feature of VOLGA is the postoperative treatment strategy. The adjuvant portion did not include chemotherapy; it relied on immunotherapy after surgery. Dr. Drakaki emphasizes that this design may help clarify the role of postoperative immune treatment after a neoadjuvant antibody-drug conjugate and immunotherapy approach.
“The very important point to make [is] the adjuvant portion of the trial does not have chemotherapy,” Dr. Drakaki explains. “It’s only immunotherapy. And we know that complementing the treatment with this adjuvant portion is important in order to improve survival.”
If the full data confirm the topline results, VOLGA could influence preoperative discussions among medical oncologists, urologic oncologists, and patients before cystectomy. The key practical question will be whether durvalumab plus enfortumab vedotin becomes a preferred cisplatin-free perioperative option for patients who cannot receive or do not want cisplatin, and whether the tremelimumab-containing regimen should be reserved for selected patients.
Durvalumab + EV: Safety & Side Effects
Safety will be central to discussions going forward.
Enfortumab vedotin can cause side effects like:
- Skin reactions
- Neuropathy
- Hyperglycemia
- Ocular toxicity
Checkpoint inhibitors can cause immune-related side effects affecting the skin, colon, liver, lungs, endocrine glands, and other organs.
The sponsor reported that safety was consistent with the known profiles of the individual drugs and that no new safety signals were identified, but full details will be needed to judge how easily patients can complete therapy before and after cystectomy.
For Dr. Drakaki, the key is not only choosing active treatments, but also managing side effects early enough to keep patients on potentially curative therapy.
“Recognizing toxicity early on and managing toxicity early on is what will keep patients on treatment for as long as possible,” she says. “Early recognition and early intervention is what can rescue the drug and can rescue the patient.”
For now, VOLGA should be described as a positive phase 3 trial with potentially practice-changing implications, especially for cisplatin-ineligible or cisplatin-declining patients with muscle-invasive bladder cancer. But the final clinical impact is not yet established and will depend on the full presentation of hazard ratios, absolute event-free and overall survival rates, pathologic response data, surgical completion rates, and detailed safety outcomes.
Perioperative toxicities may also influence cystectomy eligibility, timing, and postoperative recovery.
