AstraZeneca’s Imfinzi plus enfortumab vedotin wins FDA approval for cisplatin-ineligible muscle-invasive bladder cancer after VOLGA Phase III survival results.
Written By: Malavatu Satvika, PharmD
Reviewed By: Pharmacally Editorial Team
AstraZeneca announced on November 13, 2026, that the US Food and Drug Administration (FDA) approved Imfinzi (durvalumab) in combination with Padcev (enfortumab vedotin-ejfv) as neoadjuvant treatment, followed by adjuvant Imfinzi monotherapy after radical cystectomy, for adults with muscle-invasive bladder cancer (MIBC) who are ineligible for or have refused cisplatin-based chemotherapy. The application was granted Priority Review and evaluated under Project Orbis, expanding perioperative Imfinzi into the cisplatin-ineligible setting following its earlier 2025 approval for cisplatin-eligible MIBC.
The approval is based on the Phase III VOLGA trial, which demonstrated statistically significant improvements in event-free survival (EFS) and overall survival (OS). The regimen reduced the relative risk of an EFS event by 49% and the risk of death by 42% compared with the comparator group.
Lower Risk of Recurrence-Related Events
In a planned interim analysis, the approved regimen reduced the risk of an EFS event by 49% compared with the comparator (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.38–0.67; ).
Median EFS was not reached in the Imfinzi combination group, compared with 12.1 months in the comparator group. At two years, an estimated 63.5% (64%) of patients receiving the combination remained alive and event-free, compared with 45.1% (45%) in the comparator group.
EFS was assessed through blinded independent central review and included first recurrence after radical cystectomy, first progression in patients who did not undergo surgery, failure to undergo radical cystectomy in patients with residual disease, or death from any cause. This endpoint therefore captures outcomes across the perioperative treatment pathway rather than measuring tumour response before surgery alone.
In addition, pathologic complete response (pCR) rates were substantially higher with the Imfinzi combination at 45.1%, compared with 9.6% in the comparator group, reflecting stronger pre-surgical tumour clearance.
The 49% reduction represents a relative reduction in the hazard of an EFS event over follow-up. It does not mean that 49% more patients were cured.
Overall Survival Also Improved
Overall survival, a key secondary endpoint, also favoured the Imfinzi combination. The risk of death was reduced by 42% compared with the comparator (HR, 0.58; 95% CI, 0.40–0.83; ).
Median OS had not been reached in either group at the analysis. Estimated two-year survival was 78.4% (78%) with the Imfinzi combination and 69.4% (69%) in the comparator group.
The improvement in both EFS and OS strengthens the clinical relevance of the findings, particularly in a population with limited perioperative treatment options. However, longer follow-up will be needed to establish the durability of the survival benefit.
VOLGA: Trial Design and Treatment Approach
VOLGA (NCT04960709) was a global, randomised, open-label Phase III trial involving 695 patients with MIBC who were candidates for radical cystectomy but were ineligible for or had refused cisplatin-based chemotherapy. Participants were randomised in a 1:1:1 ratio across three treatment arms.
The approved regimen was evaluated in Arm 2 and consisted of three cycles of neoadjuvant Imfinzi plus enfortumab vedotin before radical cystectomy, followed by nine cycles of adjuvant Imfinzi monotherapy.
Arm 1 evaluated a separate regimen that additionally included tremelimumab, while Arm 3 served as the comparator, receiving radical cystectomy with or without approved adjuvant treatment.
The trial had dual primary endpoints assessing EFS for each experimental arm against the comparator. OS was a key secondary endpoint. Importantly, the FDA approval applies to the durvalumab and enfortumab vedotin regimen without tremelimumab. Outcomes from the three-drug arm should not be attributed to the approved combination.
Safety, Surgical Feasibility, and Patient-Reported Quality of Life
The safety and tolerability of Imfinzi plus enfortumab vedotin were consistent with the known safety profiles of the individual medicines, with no new safety signals identified.
Grade 3 or 4 adverse events from any cause occurred in 64% of patients receiving the combination and 44% in the comparator group, according to AstraZeneca’s reported analysis. These figures represent all-cause adverse events rather than treatment-related events alone. Common adverse reactions associated with the regimen included skin reactions and rash, pruritus, fatigue, peripheral neuropathy, diarrhea, and immune-mediated adverse events.
Crucially for perioperative care, adverse events delayed radical cystectomy in only 4% of patients treated with the combination, indicating that neoadjuvant systemic therapy rarely compromised surgical timing. Patient-reported quality of life was also maintained after surgery among patients treated with the combination, an important consideration in a treatment pathway involving major surgery and systemic therapy.
Clinical Interpretation
The VOLGA findings support a perioperative strategy combining an antibody-drug conjugate with PD-L1 inhibition before surgery, followed by continued immunotherapy after surgery. Enfortumab vedotin delivers a cytotoxic payload to cells expressing Nectin-4, while durvalumab blocks PD-L1 interactions with PD-1 and CD80, helping counter tumour-mediated immune suppression.
The clinical significance of this approval lies in extending a systemic treatment option to the roughly half of MIBC patients who cannot receive or have refused cisplatin-based chemotherapy. The simultaneous improvements in pCR, EFS, and OS provide evidence of benefit beyond tumour response alone in this defined population.
However, VOLGA did not directly compare the approved regimen with cisplatin-based perioperative treatment. Its findings should therefore not be generalised to cisplatin-eligible patients or other bladder cancer stages. The open-label design and interim nature of the reported analysis also make continued follow-up important, particularly because median OS has not yet been reached.
Overall, the approval introduces a new perioperative treatment option for cisplatin-ineligible patients with MIBC. Longer follow-up will help clarify the durability of survival benefit and the longer-term safety profile.
Reference
Perioperative Imfinzi approved in the US in novel regimen with neoadjuvant enfortumab vedotin for patients with muscle-invasive bladder cancer, Astra Zeneca, 13 November 2026
Treatment Combination of Durvalumab, Tremelimumab and Enfortumab Vedotin or Durvalumab and Enfortumab Vedotin in Patients with Muscle Invasive Bladder Cancer Ineligible to Cisplatin or Who Refuse Cisplatin (VOLGA), ClinicalTrials.gov ID NCT04960709
About the Writer
Malavatu Satvika (Linkedin) is a Pharm.D professional and aspiring healthcare medical writer with clinical exposure and research experience. Her interests include medical writing, drug safety, pharmaceutical research, and evidence-based healthcare communication. She has contributed to two research publications in pharmaceutical journals and has gained practical experience in prescription review, patient counselling, medication review, adverse drug reaction monitoring, drug information services, literature review, and clinical documentation through regular hospital training.
She has completed certifications in clinical research, ICH-GCP E6(R3), data management for clinical research, and congenital hypothyroidism. With a strong foundation in pharmacy, clinical practice, and scientific research, she aims to translate complex medical and pharmaceutical information into accurate, clear, and evidence-based healthcare content. She is also preparing to pursue a PhD and further develop her expertise in medical writing and pharmaceutical research.