Durvalumab + EV Around Surgery Cut the Risk of Bladder Cancer Events by 49% and of Death by 42%: VOLGA Results at ESMO 2026
In this article
VOLGA: Does durvalumab plus enfortumab vedotin around surgery improve outcomes in muscle-invasive bladder cancer?
Medical content reviewed by Prof. Dr. Mustafa Özdoğan · Last updated: October 2026
The VOLGA phase 3 trial, presented at ESMO 2026 Presidential Symposium I (LBA2) and published at the same time in the New England Journal of Medicine, tested durvalumab plus enfortumab vedotin (EV) around radical cystectomy in muscle-invasive bladder cancer patients who cannot or will not receive cisplatin. Versus surgery with or without adjuvant therapy, it cut the risk of an event by 49% (HR 0.51) and of death by 42% (HR 0.58). It is not yet approved.
- Primary endpoint (event-free survival): HR 0.51 (95% CI 0.38–0.67; p<0.0001). Median not reached vs 12.1 months; at 24 months 64% vs 45% were event-free: an absolute difference of 19 points, or roughly one event avoided for every 5 patients at 2 years.
- Overall survival (key secondary, interim analysis): HR 0.58 (95% CI 0.40–0.83; p=0.0027); 24-month overall survival 78% vs 69% (9 points). Pathologic complete response 45% vs 10% (local review).
- Triplet with tremelimumab: EFS HR 0.61 (95% CI 0.47–0.80), but overall survival was not significant (HR 0.77; 95% CI 0.54–1.07; p=0.123) and toxicity was higher, so the durvalumab + EV doublet is the regimen in focus.
- Limits: open-label, planned interim analysis, median EFS follow-up 22.9 months; the control arm was surgery (± adjuvant), not pembrolizumab + EV; grade 3–4 adverse events from any cause were 64% vs 44%. Not approved yet (FDA priority review).
Why does this matter?
Up to half of patients with muscle-invasive bladder cancer cannot receive cisplatin-based chemotherapy (statement by the trial's coordinating investigator). For them, radical cystectomy alone has long been the standard, and recurrence after surgery is common: in VOLGA, the control arm's median event-free survival was only 12.1 months. Adding effective treatment before and after surgery is therefore a major unmet need.
This is not the first perioperative immunotherapy–antibody–drug conjugate regimen. The FDA approved pembrolizumab + EV for cisplatin-ineligible muscle-invasive bladder cancer on 21 November 2025 (KEYNOTE-905: EFS HR 0.40, OS HR 0.50 vs surgery alone) and extended it to all cystectomy candidates on 10 July 2026 (KEYNOTE-B15: EFS HR 0.53, OS HR 0.65 vs gemcitabine + cisplatin). VOLGA tests a different checkpoint inhibitor, the PD-L1 antibody durvalumab, with only three neoadjuvant EV cycles. AstraZeneca calls it its third positive bladder cancer readout; the FDA granted priority review on 25 September 2026.
How is durvalumab plus enfortumab vedotin given in muscle-invasive bladder cancer?
In VOLGA, patients who could not or would not receive cisplatin got three cycles of durvalumab plus EV before radical cystectomy and nine cycles of durvalumab afterwards. Compared with surgery alone or with approved adjuvant therapy, the risk of an event fell by 49% and the risk of death by 42%. The regimen is not yet approved.
How was the VOLGA trial conducted?
VOLGA is a randomized, open-label phase 3 trial (NCT04960709). Patients were randomized 1:1:1 to two experimental regimens or to surgery.
| Feature | Details |
|---|---|
| Design | Phase 3, randomized 1:1:1, open-label, multicenter; 182 centers in 25 countries |
| Patients | 695 patients: 233 durvalumab + EV, 233 durvalumab + tremelimumab + EV, 229 control |
| Population | Muscle-invasive bladder cancer (cT2–T4aN0/1M0 or cT1N1M0), candidates for radical cystectomy, ineligible for or declining cisplatin; ECOG 0–2; no prior systemic therapy for muscle-invasive disease |
| Durvalumab + EV | Before surgery: 3 cycles of durvalumab 1500 mg + EV 1.25 mg/kg every 3 weeks; radical cystectomy; after surgery: 9 cycles of durvalumab |
| Durvalumab + tremelimumab + EV | The same regimen plus tremelimumab: 2 cycles before surgery and 1 cycle after surgery |
| Control | Radical cystectomy, then observation or locally approved adjuvant therapy |
| Primary endpoints | Event-free survival (blinded independent central review) for each experimental arm vs control. Events: recurrence after cystectomy, progression or failure to undergo cystectomy in residual disease, or death from any cause |
| Key secondary endpoints | Overall survival; also pathologic complete response, disease-free survival, pathologic downstaging, safety |
| Analysis | First planned interim analysis, data cutoff 2 March 2026; median EFS follow-up 22.9 months |
Figure 1 · How were the arms organized?
VOLGA trial flow (simplified)
What were the survival and response results?
All comparisons below are between arms of the same trial and therefore direct. Colored bars are durvalumab + EV, the dark bar is the triplet with tremelimumab, and gray bars are the control arm.
Efficacy at 12 and 24 months and pathologic response
VOLGA · interim analysis
Event-free survival · 24 months
Event-free survival · 12 months
Overall survival · 24 months
Pathologic complete response (local review)
For 12-month EFS, 24-month overall survival and pCR only durvalumab + EV vs control values were available; triplet-arm values were not reported. Both experimental arms share the same control arm.
| Endpoint | Durvalumab + EV vs control | Durvalumab + tremelimumab + EV vs control |
|---|---|---|
| Event-free survival (primary) | HR 0.51 (0.38–0.67); p<0.0001 | HR 0.61 (0.47–0.80); p=0.0004 |
| Median EFS | Not reached (95% CI 33.2–NC) vs 12.1 months (7.6–27.0) | Not reported |
| EFS events | 84 (36%) vs 123 (54%) | Not reported |
| EFS at 12 months | 73% vs 50% | Not reported |
| EFS at 24 months | 64% vs 45% | 60% vs 45% |
| Overall survival (key secondary) | HR 0.58 (0.40–0.83); p=0.0027 | HR 0.77 (0.54–1.07); p=0.123 (not significant) |
| Deaths | 49 (21%) vs 74 (32%) | Not reported |
| Overall survival at 24 months | 78% vs 69% | Not reported |
| Pathologic complete response | 45% (95% CI 38.6–51.7) vs 10% (6.1–14.2) | Not reported |
NC = not calculable. Median overall survival was not reached in either arm. This is a planned interim analysis; follow-up continues. Pathologic complete response was assessed by local review and is a secondary endpoint.
What did the circulating tumor DNA analysis show?
In an exploratory analysis of 112 patients, 60% of those with detectable circulating tumor DNA (ctDNA) at baseline cleared it before surgery. Their 24-month event-free survival was 81%, compared with 55% in those whose ctDNA persisted. This was not randomized and is hypothesis-generating; it should not be used for treatment decisions.
Did adding tremelimumab help?
Adding the CTLA-4 inhibitor tremelimumab also improved event-free survival against control (HR 0.61), but overall survival was not significantly better at this interim analysis (HR 0.77; 95% CI 0.54–1.07; p=0.123). The triplet was also more toxic: grade 3–4 adverse events from any cause occurred in 70% (vs 64% with the doublet), possibly treatment-related grade 3–4 events in 42% (vs 30%), and treatment-related events leading to death in 5 patients (2%) vs 1 patient (0.4%).
The presenting investigator suggested that the extra toxicity may explain the smaller overall survival gain; this is an interpretation, not a tested finding, and the two experimental arms were not compared head-to-head as a primary endpoint. The investigators presented the durvalumab + EV doublet as the potential new standard of care.
Did patients still reach surgery and complete treatment?
Because treatment starts before surgery, it matters whether patients still reach cystectomy. In the doublet arm 85% did, compared with 78% in the control arm. Only about half completed the adjuvant phase.
| Measure | Durvalumab + EV | Durvalumab + tremelimumab + EV | Control |
|---|---|---|---|
| Radical cystectomy completed | 85% | 79% | 78% |
| Adjuvant treatment completed | 55% | 42% | Not reported |
What are the most common side effects during treatment?
Investigators described the safety profiles as consistent with those of the individual agents, with no new safety signals. Severe events were clearly more frequent with the experimental regimens than with surgery alone.
Severe and serious adverse events
VOLGA · interim analysis
Grade 3–4 adverse events (any cause)
Possibly treatment-related grade 3–4 events
Serious possibly treatment-related events
Possibly treatment-related events leading to death
Only the first group includes the control arm; for treatment-related events the control arm was not reported. Red bars mark severe events that need attention. Comparisons are within the same trial.
| Measure | Durvalumab + EV | Durvalumab + tremelimumab + EV | Control |
|---|---|---|---|
| Grade 3–4 adverse events, any cause | 64% | 70% | 44% |
| Possibly treatment-related grade 3–4 events | 30% | 42% | Not reported |
| Serious possibly treatment-related events | 20% | 31% | Not reported |
| Possibly treatment-related events leading to death | 1 patient (0.4%) | 5 patients (2%) | Not reported |
| Immune-mediated adverse events* | 33% | Not reported | 3% |
| Treatment discontinuation for an adverse event* | 21% | Not reported | Not reported |
*Reported by a single secondary source. According to AstraZeneca, patient-reported quality of life was maintained after surgery in the doublet arm. The sources do not detail enfortumab vedotin-specific events such as peripheral neuropathy and skin reactions; these are known to need monitoring and should be checked in the full publication.
How do these results compare with other perioperative EV regimens?
Two pembrolizumab + EV regimens are already approved by the FDA. The table puts the three trials side by side, but they are not directly comparable.
| Trial | Comparison and population | EFS HR (95% CI) | OS HR (95% CI) | Regulatory status |
|---|---|---|---|---|
| KEYNOTE-905 / EV-303 (n=344) | Pembrolizumab + EV vs surgery alone; cisplatin-ineligible or declining | 0.40 (0.28–0.57) | 0.50 (0.33–0.74) | FDA approved 21 Nov 2025 |
| KEYNOTE-B15 / EV-304 (n=808) | Pembrolizumab + EV vs gemcitabine + cisplatin; cisplatin-eligible | 0.53 (0.41–0.70) | 0.65 (0.48–0.89) | FDA approved 10 Jul 2026 (all cystectomy candidates) |
| VOLGA (n=462 in the doublet and control arms) | Durvalumab + EV vs surgery ± adjuvant; cisplatin-ineligible or declining | 0.51 (0.38–0.67) | 0.58 (0.40–0.83) | Not approved; FDA priority review granted 25 Sep 2026 |
The comparison is indirect: different checkpoint inhibitors, control arms, populations and follow-up. No trial has compared durvalumab + EV with pembrolizumab + EV, so no conclusion about which is better can be drawn.
What is established and what is still uncertain?
Figure 2 · Evidence map
VOLGA, ESMO 2026 LBA2
- Approval: Durvalumab + EV for muscle-invasive bladder cancer is not approved anywhere. The FDA granted priority review on 25 September 2026 for patients who cannot or will not receive cisplatin, with an action date in the fourth quarter of 2026; applications are under review in the EU, Japan and other countries (OncLive).
- Alternatives that are approved: Pembrolizumab + EV has been FDA-approved as a perioperative regimen since November 2025 (cisplatin-ineligible) and July 2026 (all cystectomy candidates). Availability and reimbursement vary by country and must be checked locally.
- Access: The sources do not mention an access route outside clinical trials.
- What should patients do? Treatment of muscle-invasive bladder cancer is planned in a multidisciplinary tumor board according to stage, kidney function, cisplatin eligibility and overall condition. Discuss with your oncologist and urologist which options are currently available.
Frequently asked questions
- Is durvalumab plus enfortumab vedotin available now?
- Not as an approved treatment. The FDA granted priority review on 25 September 2026 with an action date in the fourth quarter of 2026, and applications are under review in other regions. Approved alternatives, such as pembrolizumab + EV, exist in some countries.
- Did it improve overall survival or only recurrence?
- Both were improved at this interim analysis: event-free survival HR 0.51 and overall survival HR 0.58 (24-month overall survival 78% vs 69%). Follow-up continues and the control arm was surgery with or without adjuvant therapy.
- Is it better than pembrolizumab plus EV?
- Unknown. No trial has compared the two regimens directly, and the trials differ in populations, control arms and follow-up, so indirect comparison is unreliable.
- What are the main side effects?
- Grade 3–4 adverse events from any cause occurred in 64% of patients with durvalumab + EV vs 44% with surgery alone. Possibly treatment-related grade 3–4 events were 30%; one treatment-related event led to death (0.4%).
Glossary
- Perioperative therapy
- Treatment given before surgery (neoadjuvant) and after surgery (adjuvant).
- Radical cystectomy
- Surgical removal of the bladder and nearby tissues.
- Event-free survival (EFS)
- Time from randomization to recurrence, progression, failure to undergo surgery, or death from any cause.
- Pathologic complete response (pCR)
- No viable tumor found in the surgical specimen after pre-operative treatment.
- Enfortumab vedotin (EV)
- An antibody–drug conjugate that delivers a cell-killing agent to cells carrying the protein nectin-4.
- Immune checkpoint inhibitor
- A drug such as durvalumab (PD-L1) or tremelimumab (CTLA-4) that releases the brakes on the immune system.
- Hazard ratio (HR)
- A value below 1 means lower risk of the event in the experimental arm; 0.51 equals roughly a 49% lower risk.
DROZDOGAN Academy Commentary
VOLGA shows that a second perioperative immunotherapy–EV regimen can improve event-free and overall survival over surgery in patients who cannot receive cisplatin, but it does not tell us which regimen is best.
⚡ Why it matters
For patients who cannot receive cisplatin, surgery alone has been the weak point of bladder cancer care. VOLGA adds a second positive randomized dataset to the pembrolizumab + EV experience and supports the idea that perioperative immunotherapy combined with an antibody–drug conjugate is a class effect rather than a single-drug finding.
✅ Strengths
Randomized phase 3 design; 695 patients; blinded central review of the primary endpoint; a significant overall survival result at the first interim analysis; consistent direction across event-free survival, pathologic response and survival; the surgery rate was not reduced.
⚠️ Limitations
Open-label design, interim analysis and a median EFS follow-up of only 22.9 months. The control arm (surgery with or without adjuvant therapy) differs from pembrolizumab + EV, which is now an approved perioperative option, so VOLGA cannot show superiority over it. The triplet increased toxicity without a significant overall survival gain, and several safety details come from a single secondary source.
🩺 In practice
The regimen is not approved, so it is not an available standard today. Patients with muscle-invasive bladder cancer who cannot receive cisplatin should have the approved perioperative options and clinical trials discussed in a tumor board.
❓ Open questions
How does durvalumab + EV compare with pembrolizumab + EV? Is a bladder-preserving approach possible for patients who achieve a complete response? How should the long adjuvant phase, completed by only 55%, be handled? What do peripheral neuropathy and skin toxicity look like in the full publication, and how durable is the survival benefit?
Bottom line: A strong, practice-relevant phase 3 result for cisplatin-ineligible patients; its place relative to the already approved pembrolizumab + EV remains to be defined.
- This article was prepared in October 2026.
- Figures come from the AstraZeneca press release of 24 October 2026 (accessed through a copy of the Business Wire release) and from Targeted Oncology and OncoDaily reports on the ESMO 2026 LBA2 presentation by T. Powles (24 October 2026). According to AstraZeneca the results were published simultaneously in the New England Journal of Medicine; the full text was not accessible.
- Pathologic complete response, surgery and adjuvant completion, treatment-related event rates, the triplet-arm results, immune-mediated event and discontinuation rates, the ctDNA analysis and the dosing come from a single secondary source (Targeted Oncology or OncoDaily) and were not confirmed against the full publication.
- The data come from a company-sponsored trial (AstraZeneca). The terms "practice-changing" and "potential new standard of care" are statements by the investigator and the company. The trial is open-label; pembrolizumab + EV was not a comparator.
- Early topline reports described the primary and secondary endpoints slightly differently; this article follows the ESMO session coverage and the AstraZeneca release (dual primary endpoint: event-free survival; overall survival: key secondary).
- The charts show only direct comparisons between arms of the same trial; the comparison with KEYNOTE-905 and KEYNOTE-B15 is indirect and is given as context only.
- The figures are derived from verified statements in the text and contain no new data. The Academy commentary is our own.
References
- AstraZeneca. Perioperative IMFINZI (durvalumab) plus neoadjuvant enfortumab vedotin reduced risk of recurrence by 49% and risk of death by 42% in muscle-invasive bladder cancer (VOLGA). Press release, 24 Oct 2026 (copy of the Business Wire release). https://www.stocktitan.net/news/AZN/perioperative-imfinzi-durvalumab-plus-neoadjuvant-enfortumab-vedotin-9jna54od13cc.html
- AstraZeneca. Perioperative Imfinzi plus neoadjuvant EV showed statistically significant and clinically meaningful improvements in EFS and OS in the Phase III VOLGA trial. Press release, 14 May 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/imfinzi-ev-improves-efs-os-in-bladder-cancer.html
- Powles T, et al. Perioperative durvalumab with or without tremelimumab plus neoadjuvant enfortumab vedotin in muscle-invasive bladder cancer: results from the Phase 3 VOLGA trial. ESMO Congress 2026, Madrid, Presidential Symposium I, LBA1/LBA2 session, abstract LBA2, 24 Oct 2026; simultaneous publication in N Engl J Med 2026 (per AstraZeneca).
- Targeted Oncology. ESMO 2026 Presidential Symposium I late-breaking recap (VOLGA, LBA2). Oct 2026. https://www.targetedonc.com/view/esmo-2026-presidential-symposium-i-late-breaking-recap
- OncoDaily. VOLGA at ESMO 2026: perioperative durvalumab with or without tremelimumab plus enfortumab vedotin in MIBC. Oct 2026. https://oncodaily.com/genitourinary-oncology/volga-esmo-2026
- OncLive. FDA grants priority review to perioperative durvalumab plus neoadjuvant enfortumab vedotin in MIBC. 25 Sep 2026. https://www.onclive.com/view/fda-grants-priority-review-to-perioperative-durvalumab-plus-neoadjuvant-enfortumab-vedotin-in-mibc
- U.S. Food and Drug Administration. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle-invasive bladder cancer (KEYNOTE-905/EV-303). 21 Nov 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
- U.S. Food and Drug Administration. FDA approves pembrolizumab (or with berahyaluronidase alfa-pmph) with enfortumab vedotin-ejfv for muscle-invasive bladder cancer (KEYNOTE-B15/EV-304). 10 Jul 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin
- ClinicalTrials.gov. VOLGA (NCT04960709). https://clinicaltrials.gov/study/NCT04960709
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