VOLGA Dual EFS-OS Win Masks Thin Precedent and Payer Scrutiny

Perioperative Imfinzi Plus Neoadjuvant EV Significantly Improves Survival in MIBC

AstraZeneca announced positive Phase III VOLGA trial results for its perioperative Imfinzi (durvalumab) in combination with neoadjuvant enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC) patients ineligible for or refusing cisplatin-based chemotherapy. The regimen demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and overall survival (OS) compared to standard of care. It reduced the risk of disease progression, recurrence, or death by 49% (EFS HR 0.51, p<0.0001) and the risk of death by 42% (OS HR 0.58, p=0.0027). At two years, 64% of patients were event-free and 78% were alive with the combination, versus 45% and 69% respectively in the comparator arm. The safety profile was manageable, and these findings led to FDA Priority Review.

• The VOLGA Phase III trial achieved its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in event-free survival (EFS). The perioperative Imfinzi plus neoadjuvant enfortumab vedotin regimen reduced the risk of disease progression, recurrence, not undergoing surgery, or death by 49% (HR 0.51; 95% CI 0.38-0.67; p<0.0001) compared to standard of care. At two years, an estimated 64% of patients treated with the Imfinzi combination remained alive and event-free, significantly higher than the 45% in the comparator arm, highlighting a substantial long-term benefit.
• The combination therapy also met its key secondary endpoint, showing a significant improvement in overall survival (OS), reducing the risk of death by 42% (HR 0.58; 95% CI 0.40-0.83; p=0.0027) compared to the comparator arm. This translates to an estimated 78% of patients treated with the Imfinzi combination being alive at two years, compared to 69% in the comparator arm. This clinically meaningful survival benefit underscores the potential of this novel regimen to extend lives for MIBC patients who often face limited treatment options.
• The safety and tolerability profile of the Imfinzi combination was consistent with the known profiles of the individual medicines, with no new safety signals identified. Grade 3 and 4 adverse events due to any cause occurred in 64% of patients treated with the Imfinzi combination and 44% in the comparator arm, while patient-reported quality of life was maintained. Based on these compelling findings, the Food and Drug Administration (FDA) granted perioperative Imfinzi plus neoadjuvant EV Priority Review in September 2026 for MIBC patients ineligible for or refusing cisplatin-based chemotherapy, supporting its potential as a new standard of care.

The Unmet Need for Cisplatin-Ineligible MIBC Patients

Recent literature positions cisplatin-ineligible muscle-invasive bladder cancer (MIBC) as a central unmet need, with no established perioperative standard. Platinum-based regimens improve survival but are limited to fewer than half of patients due to comorbidities, while guidelines do not exist for cisplatin-ineligible patients.

• No guideline-defined standard for cisplatin-ineligible patients: While neoadjuvant chemotherapy with perioperative immunotherapy is described as standard of care in the cisplatin-eligible population, guidelines do not exist for cisplatin-ineligible patients, defining a targeted population for novel strategies.

• Renal, functional and cardiac barriers drive non-receipt of neoadjuvant therapy: The main reasons for not receiving cisplatin-based neoadjuvant chemotherapy (NAC) were creatinine clearance <60 mL/min (40.8%), Eastern Cooperative Oncology Group performance status ≥2 (18.4%), and cardiovascular disease (18%), with NAC administered to 40% of patients and surgery without NAT/AT the most common treatment (75.9% AOK, 74.0% GWQ).

• Dedicated trial cohorts for cisplatin-ineligible MIBC: Cisplatin-ineligible patients received either avelumab alone (A) or combined with paclitaxel-gemcitabine (PG-A) in the multicenter phase 2 AURA trial (NCT03674424), with pCR rates of 14% (95% CI: 6% to 31%) in the PG-A arm and 32% (95% CI: 18% to 51%) in the A arm.

• Inferior long-term outcomes in cisplatin-ineligible cohorts: The 36-month OS rates were 48% (95% CI: 33% to 71%) for PG-A and 42% (95% CI: 27% to 65%) for A, compared with 87% (95% CI: 76% to 98%) for ddMVAC-A and 67% (95% CI: 53% to 84%) for GC-A in the cisplatin-eligible cohort.

VOLGA Phase III: Unpacking Design and Landmark Outcomes

Key perioperative trials in muscle-invasive bladder cancer have compared dose-dense methotrexate, vinblastine, doxorubicin and cisplatin versus gemcitabine and cisplatin in the neoadjuvant setting. VESPER evaluated long-term survival endpoints at 5 years, while SWOG S1314 evaluated COXEN biomarker prediction and pathologic response.

Evolving the MIBC Treatment Landscape with Perioperative Imfinzi

For decades, cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy with pelvic lymphadenectomy was the standard of care for cisplatin-eligible muscle-invasive bladder cancer, with neoadjuvant chemotherapy improving overall survival compared to radical cystectomy alone. This paradigm was redefined by perioperative immune checkpoint inhibition. In the NIAGARA trial, perioperative durvalumab plus gemcitabine and cisplatin outperformed gemcitabine and cisplatin alone in terms of pathological complete response rates, overall survival (HR: 0.75), and event-free survival (HR: 0.68). The regimen evaluated neoadjuvant gemcitabine and cisplatin plus durvalumab followed by radical cystectomy and adjuvant durvalumab monotherapy, and demonstrated improvement in event-free survival and overall survival for patients with muscle-invasive bladder cancer.

Refinement of cytotoxic and adjuvant strategies occurred in parallel. In the VESPER trial, dose-dense methotrexate, vinblastine, doxorubicin and cisplatin provided oncological benefits over gemcitabine and cisplatin alone in terms of pathological complete response rates, overall survival (HR: 0.71), and progression-free survival (HR: 0.70), with differential safety profiles in hematologic toxicity reported between dose-dense methotrexate, vinblastine, doxorubicin and cisplatin and durvalumab plus gemcitabine and cisplatin regimens. In the adjuvant setting, nivolumab was shown to extend disease-free and overall survival compared with placebo for patients at high risk for disease recurrence after radical cystectomy in the CheckMate 274 trial, and two phase 3 studies of adjuvant immune checkpoint inhibition with nivolumab and pembrolizumab have both reported a doubling of disease-free survival in patients with high-risk muscle-invasive bladder cancer receiving therapy.

Antibody-drug conjugate combinations have established a further perioperative standard. The phase III trials KEYNOTE-905/EV-303 and KEYNOTE-B15/EV-304 have established perioperative enfortumab vedotin plus pembrolizumab as a new standard of care for neoadjuvant therapy. In KEYNOTE-B15/EV-304, 405 participants were assigned to receive enfortumab vedotin-pembrolizumab and 403 to receive cisplatin-gemcitabine, with median time from randomization to data-cutoff of 33.6 months. At 2 years, estimated event-free survival was 79.4% with enfortumab vedotin-pembrolizumab and 66.2% with cisplatin-gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval, 0.41 to 0.70; P<0.001), estimated overall survival was 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% confidence interval, 0.48 to 0.89), and pathological complete response occurred in 55.8% and 32.5% of participants. The incidence of grade 3 or higher adverse events of any cause was 75.7% with enfortumab vedotin-pembrolizumab and 67.2% with cisplatin-gemcitabine.

A New Horizon for Cisplatin-Ineligible MIBC Patients

The recent positive Phase III VOLGA trial results for perioperative durvalumab in combination with neoadjuvant enfortumab vedotin (EV) mark a significant advancement in the treatment of muscle-invasive bladder cancer (MIBC), particularly for patients ineligible for or refusing cisplatin-based chemotherapy. This population has historically faced limited effective systemic treatment options, often proceeding directly to radical cystectomy with poor long-term survival outcomes, sometimes with median overall survival under two years. The observed statistically significant and clinically meaningful improvements in event-free survival and overall survival with this novel combination represent a potential paradigm shift, offering a much-needed new option for a vulnerable patient group.

This development underscores the growing importance of combination strategies, particularly integrating antibody-drug conjugates (ADCs) like enfortumab vedotin, which targets Nectin-4 highly expressed in urothelial carcinoma, with immune checkpoint inhibitors (ICIs) such as durvalumab. Research indicates that enfortumab vedotin can upregulate PD-L1 expression, suggesting a mechanistic synergy that may enhance immune responses. The success of this perioperative regimen, following the established efficacy of enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma, further validates the strategic direction of combining these powerful modalities in earlier disease stages.

However, the implementation of such advanced regimens comes with considerations. Managing the distinct and potentially overlapping adverse event profiles of enfortumab vedotin (e.g., skin reactions, peripheral neuropathy, hyperglycemia) and immune checkpoint inhibitors is crucial for patient safety and treatment adherence. While Nectin-4 expression is a known target, the optimal selection of patients who will derive the greatest benefit from this specific combination in the perioperative setting, potentially through robust biomarkers like circulating tumor DNA, remains an area for ongoing refinement. The long-term durability of these benefits and real-world effectiveness will also be key factors as this regimen moves towards clinical practice.