New drug combination improves survival in patients with muscle-invasive bladder cancer

by Denise Heady, University of California, Los Angeles

edited by Gaby Clark, reviewed by Andrew Zinin

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A new treatment approach could help people with an aggressive form of bladder cancer live longer and reduce the chances of their cancer returning or progressing, particularly those who cannot receive standard chemotherapy, according to findings from a large international clinical trial co-led by researchers at the UCLA Health Jonsson Comprehensive Cancer Center.

The study, published in the New England Journal of Medicine, found that patients who received a combination of the immunotherapy drug durvalumab and the targeted cancer drug enfortumab vedotin before bladder removal surgery, followed by immunotherapy after surgery, had a 42% lower risk of death compared with patients who underwent surgery alone. The treatment also reduced the risk of cancer returning or progressing or of other cancer-related events, including death, by 49%.

The findings offer a promising new treatment approach for patients who are unable to receive cisplatin-based chemotherapy, a standard treatment commonly given before bladder removal surgery to help reduce the risk of cancer returning.

"Nearly half of patients with muscle-invasive bladder cancer are unable to receive standard cisplatin-based chemotherapy, leaving them with limited treatment options," said Dr. Alexandra Drakaki, professor of medicine and urology at the David Geffen School of Medicine at UCLA and senior author of the study. "These findings give us an opportunity to offer these patients an effective treatment before surgery, with the goal of improving their chances of long-term survival."

Muscle-invasive bladder cancer is an aggressive form of the disease that has grown into the muscular wall of the bladder. Treatment typically involves surgery to remove the bladder, often preceded by chemotherapy to shrink the cancer and reduce the risk of recurrence.

However, many patients cannot receive cisplatin-based chemotherapy because of kidney problems, hearing loss, nerve damage or other health conditions. Historically, these patients often proceeded directly to surgery without receiving cancer-fighting drugs beforehand, putting them at greater risk of their cancer returning or spreading.

Recent advances in immunotherapy and targeted cancer treatments have begun to expand options for these patients. This research builds on that progress by testing whether combining immunotherapy with enfortumab vedotin, a type of targeted treatment known as an antibody-drug conjugate, could improve outcomes when given before surgery.

Enfortumab vedotin works by attaching to a protein called nectin-4, found on many bladder cancer cells, and delivering a cancer-killing drug directly to those cells. Durvalumab works differently, helping the body's immune system recognize and attack cancer by blocking a protein called PD-L1 that tumors can use to evade immune detection.

By combining these approaches, researchers hoped to attack cancer cells directly while also strengthening the immune system's ability to fight the disease.

To evaluate whether this approach could improve outcomes, investigators conducted a large international phase 3 clinical trial, known as VOLGA, involving 695 patients with muscle-invasive bladder cancer across 229 medical centers in 25 countries. All participants were unable to receive standard cisplatin-based chemotherapy or refused to receive it.

Patients were randomly assigned to one of three groups. The first group received durvalumab and enfortumab vedotin before bladder removal surgery, followed by durvalumab alone after surgery. The second group received the same treatment with the addition of another immunotherapy drug, tremelimumab. The third group underwent surgery alone without the study drug combinations.

The researchers then evaluated how long patients lived without their cancer returning or progressing, as well as overall survival, treatment response and side effects.

The researchers found that patients who received durvalumab and enfortumab vedotin had significantly better outcomes than those who underwent surgery alone.

At two years, 78.4% of patients receiving the two-drug combination were alive, compared with 69.4% of patients who underwent surgery alone. The treatment also helped patients remain free of cancer recurrence or progression for longer, with 63.5% of patients in the combination group experiencing no cancer-related events at two years, compared with 45.1% in the surgery-alone group.

The combination was also particularly effective at eliminating detectable cancer before surgery. Researchers found that 45.1% of patients receiving the two-drug treatment had no detectable cancer remaining in the tissue examined after surgery, compared with just 9.6% of patients who underwent surgery alone.

The three-drug combination that included tremelimumab also significantly reduced the risk of cancer-related events or death compared with surgery alone, but did not show a statistically significant improvement in overall survival at this stage of the study.

Severe side effects were more common among patients receiving the drug combinations. However, the researchers reported no unexpected safety problems with the two-drug treatment, and it did not appear to increase complications related to surgery.

One of the distinguishing features of the VOLGA trial is that patients received enfortumab vedotin only before surgery, rather than both before and after surgery as in other recently studied treatment approaches. Following surgery, patients continued with immunotherapy alone, potentially reducing the burden of additional treatment and treatment-related toxicity during recovery from bladder removal, a major operation that can significantly affect patients' quality of life.

"What makes this approach particularly important is that patients don't have to continue receiving the targeted cancer drug after surgery, when they're recovering and trying to return to their normal lives," Drakaki said. "We are seeing meaningful survival benefits with immunotherapy alone after surgery, which could help reduce the treatment and financial burden for patients during an already challenging time."

Drakaki noted that longer follow-up is needed to determine whether the three-drug combination of enfortumab vedotin, durvalumab and tremelimumab improves overall survival. In the meantime, the current findings are encouraging and support the combination of durvalumab and enfortumab vedotin as a potential new treatment option for patients with muscle-invasive bladder cancer who are unable or unwilling to receive standard cisplatin-based chemotherapy.

Publication details

Thomas Powles et al., Durvalumab, Tremelimumab, and Enfortumab Vedotin in Muscle-Invasive Bladder Cancer, New England Journal of Medicine (2026). DOI: 10.1056/nejmoa2608323

Journal information: New England Journal of Medicine

Key medical concepts

durvalumabenfortumab vedotinOverall SurvivalCystectomy

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OncologyUrology Provided by University of California, Los Angeles Who's behind this story?

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