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In the phase III VOLGA trial, perioperative durvalumab plus three pre-surgery cycles of enfortumab vedotin improved event-free and overall survival versus radical cystectomy alone in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin. The triplet regimen with tremelimumab improved event-free survival but has not shown a statistically significant overall-survival benefit; serious adverse events were more frequent in both treatment groups than in the control group.
The phase III VOLGA trial found that perioperative durvalumab plus enfortumab vedotin improved event-free and overall survival compared with radical cystectomy alone in people with muscle-invasive bladder cancer who could not tolerate or chose not to receive cisplatin. At 24 months, event-free survival was 63.5% versus 45.1%, and overall survival was 78.4% versus 69.4%, according to results presented at the European Society for Medical Oncology congress in Madrid and published in the New England Journal of Medicine.
The doublet’s event-free survival advantage corresponded to a hazard ratio of 0.51 (95% confidence interval 0.38-0.67; P<0.001), while the overall-survival hazard ratio was 0.58 (95% CI 0.40-0.83; P=0.003). Event-free survival measures the time until events such as disease progression or recurrence; the trial report also included not undergoing cystectomy in the presence of residual disease and death among the relevant events.
VOLGA randomized 695 patients at 229 sites across 25 countries. One treatment group received three cycles of durvalumab and enfortumab vedotin before surgery, followed by durvalumab after surgery. A second group added tremelimumab before and after surgery. The control group received radical cystectomy. About 76.1% were cisplatin-ineligible; the remaining 23.9% had declined cisplatin. Participants had a median age of about 72, and most were men.
The triplet regimen also improved event-free survival versus control, with a hazard ratio of 0.61 (95% CI 0.47-0.80; P<0.001), but its overall-survival result was not statistically significant: HR 0.77 (95% CI 0.54-1.07; P=0.12). Complete responses were reported in 45.1% with the doublet, 42.9% with the triplet and 9.6% in the control group. These results do not establish that the triplet improves overall survival.
A New Perioperative Option for Cisplatin-Ineligible Patients
The findings address a group with limited treatment options: people with muscle-invasive bladder cancer who cannot receive cisplatin-based chemotherapy or decide against it. The survival results suggest that a regimen combining an immune checkpoint inhibitor with enfortumab vedotin may improve outcomes around surgery compared with surgery alone. That matters because bladder cancer can recur or progress even after an operation, and the trial measured outcomes beyond the immediate surgical period.
The regimen also uses three cycles of enfortumab vedotin before surgery, rather than continuing that drug after the operation. Lead investigator Thomas Powles said the results may inform discussion about treatment duration. However, the trial does not establish that every patient should receive this approach, nor does the reported comparison by itself settle how it should fit alongside other available regimens. Treatment decisions require consideration of patient eligibility, risks and the full evidence base.
Safety is part of that decision. Grade 3 or higher adverse events occurred in 71.1% with the doublet, 79.5% with the triplet and 50.2% in the control group. The survival gains must be weighed against these higher rates of serious adverse events and the effects of treatment before and after major surgery.
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How VOLGA Tested Treatment Around Surgery
Perioperative treatment includes therapy before surgery, known as neoadjuvant treatment, and treatment afterward, known as adjuvant treatment. In VOLGA, durvalumab was given before and after surgery, while enfortumab vedotin was used in three preoperative cycles. The investigators described the approach as concentrating enfortumab vedotin before the demands of surgery while giving immunotherapy on both sides of the operation.
The results follow other trials testing drug combinations in this setting. ESMO discussant Michiel van der Heijden pointed to KEYNOTE-905, which found improved event-free and overall survival with perioperative enfortumab vedotin plus pembrolizumab compared with radical cystectomy in cisplatin-ineligible patients. He also cited KEYNOTE B-15, which reported benefits for that combination over standard chemotherapy in cisplatin-eligible patients. Those studies provide context, but they tested different regimens and populations; their results should not be treated as direct head-to-head comparisons with VOLGA.
Powles and colleagues wrote that the findings support combining an immune checkpoint inhibitor with enfortumab vedotin and could inform discussion of treatment duration. Van der Heijden described the VOLGA findings as adding an option for this disease setting. Those are interpretations of the trial’s implications, not a determination of how treatment guidelines or practice will change.
“Shorter periods of systemic therapy are associated with great outcomes.”
— Thomas Powles, MD, VOLGA investigator, speaking at ESMO
The Triplet’s Survival Benefit Remains Unproven
Although adding tremelimumab improved event-free survival, VOLGA has not shown a statistically significant overall-survival improvement for the triplet. The confidence interval for that outcome crossed 1, and the reported P value was 0.12. The trial results therefore do not support describing the triplet as having an established overall-survival benefit.
There were also more serious adverse events with the triplet than with the doublet: grade 3 or higher events affected 79.5% versus 71.1% of patients. The report said grade 3 or 4 immune-mediated events occurred in 20% of triplet patients and 11% of doublet patients; adverse events leading to discontinuation of enfortumab vedotin occurred in 23% and 11%, respectively. Powles suggested that added toxicity may help explain why the triplet results were not as strong as the doublet’s, but that is an interpretation rather than a proven explanation.
The available report does not specify how regulators or clinical guidelines will respond, or provide enough detail to determine which individual patients are best suited to each approach. Longer-term follow-up and further clinical discussion may add information about durability, risks and treatment selection.
Follow-Up and Treatment Guidance
The immediate next step is continued evaluation of the VOLGA findings by clinicians, researchers and guideline bodies, alongside evidence from other perioperative trials. The study’s concurrent publication in the New England Journal of Medicine makes its full methods and results available for scrutiny. Further follow-up will be needed to clarify how durable the survival differences are and how benefits and adverse effects balance over time.
For patients and care teams, the relevant discussion is not simply whether a regimen improved trial outcomes, but how those results apply to an individual’s health, cisplatin eligibility, surgical plan and tolerance for treatment. The supplied report does not announce a regulatory decision or a change to treatment guidelines. Until those developments are confirmed, VOLGA should be understood as phase III evidence for a potential perioperative option, with the doublet’s reported survival results and the triplet’s unresolved overall-survival outcome kept distinct.
Key Questions
What did the VOLGA trial find?
The phase III trial found better 24-month event-free and overall survival with perioperative durvalumab plus enfortumab vedotin than with radical cystectomy alone among patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin.
Did adding tremelimumab improve overall survival?
The triplet improved event-free survival versus control, but the reported overall-survival result was not statistically significant (HR 0.77; P=0.12). The trial has not established an overall-survival benefit for adding tremelimumab.
Who was included in VOLGA?
The trial enrolled 695 people with muscle-invasive bladder cancer at 229 sites in 25 countries. About 76.1% were ineligible for cisplatin, while 23.9% declined it; participants had a median age of about 72.
What were the main safety findings?
Grade 3 or higher adverse events were reported in 71.1% with durvalumab and enfortumab vedotin, 79.5% with the triplet and 50.2% with surgery alone. The trial report also said severe peripheral neuropathy was uncommon, with grade 3 or 4 cases in fewer than 1% of patients.
Has VOLGA changed standard treatment?
The source report does not announce a regulatory decision or guideline change. The results add evidence for a possible treatment option, but how they will affect recommendations and individual care remains to be determined.
Source: rss
