The European Commission has approved PADCEV (enfortumab vedotin) plus Keytruda (pembrolizumab) as the first perioperative treatment for cisplatin-ineligible muscle-invasive bladder cancer, supported by Phase 3 EV-303/KEYNOTE-905 trial results.
Written By: Kalyani Boharapi,
M.Pharm (Reg. Affairs)
Reviewed By: Pharmacally Editorial Team
The European Commission has approved PADCEV (enfortumab vedotin) in combination with Keytruda (pembrolizumab) as perioperative treatment for adults with resectable muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-containing chemotherapy.
The approval allows the combination to be administered as neoadjuvant therapy before radical cystectomy and continued as adjuvant treatment after surgery. It establishes the first approved perioperative treatment option for cisplatin-ineligible patients with MIBC in the European Union.
The decision is supported by data from the Phase 3 EV-303/KEYNOTE-905 trial (NCT03924895), which demonstrated significant improvements in event-free survival (EFS) and overall survival (OS) compared with surgery alone.
PADCEV Expands Treatment Options in MIBC
Muscle-invasive bladder cancer accounts for approximately 30% of all bladder cancer cases and carries a substantial risk of recurrence despite surgery with curative intent. Nearly half of patients with MIBC are unable to receive cisplatin-based chemotherapy because of age, renal impairment, or other comorbidities.
Until now, these patients had no approved perioperative treatment options beyond surgery in the European Union.
PADCEV is a first-in-class antibody-drug conjugate directed against Nectin-4, a protein highly expressed on bladder cancer cells. After binding to Nectin-4, the therapy delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent that induces cell cycle arrest and apoptosis. Pembrolizumab, a PD-1 inhibitor, enhances anti-tumor immune responses, providing a complementary mechanism of action.
EV-303/KEYNOTE-905 Trial Results
EV-303/KEYNOTE-905 is an ongoing global, randomized, open-label Phase 3 study evaluating perioperative enfortumab vedotin plus pembrolizumab in patients with MIBC who were ineligible for or declined cisplatin-containing chemotherapy.
Patients were randomized to receive perioperative pembrolizumab alone, surgery alone, or perioperative enfortumab vedotin plus pembrolizumab.
The combination met the primary endpoint of event-free survival. Treatment reduced the risk of disease recurrence, progression, or death by 60% compared with surgery alone (HR 0.40; 95% CI: 0.28–0.57; p<0.0001).
The regimen also delivered a significant overall survival benefit, reducing the risk of death by 50% versus surgery alone (HR 0.50; 95% CI: 0.33–0.74; p=0.0002).
These findings indicate that perioperative treatment with enfortumab vedotin and pembrolizumab can substantially improve long-term outcomes in a patient population with limited therapeutic options.
Safety Findings
The safety profile of the combination was consistent with the known safety profiles of the individual agents, and investigators reported no new safety signals.
The most common treatment-related adverse events occurring in at least 30% of patients included pruritus, alopecia, diarrhea, fatigue, and anemia.
Results from EV-303/KEYNOTE-905 were recently published in the New England Journal of Medicine.
Clinical Significance of the Approval
Moitreyee Chatterjee-Kishore, Executive Vice President and Head of Oncology Development at Astellas, stated that the approval addresses a long-standing unmet need for patients who cannot receive cisplatin-based chemotherapy and provides a new treatment option capable of improving outcomes before and after surgery.
EV-303 principal investigator Dr. Christof Vulsteke highlighted the high recurrence risk associated with MIBC despite curative-intent surgery and noted that the trial demonstrated clinically meaningful improvements in both event-free and overall survival.
Patient advocacy groups also welcomed the approval, citing the limited treatment choices previously available for cisplatin-ineligible patients facing a significant risk of disease recurrence.
Regulatory Impact
The approval expands the use of enfortumab vedotin plus pembrolizumab beyond advanced urothelial cancer into earlier-stage disease with curative intent. The combination is already approved in Europe for adults with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy.
Astellas is working with health technology assessment bodies and reimbursement authorities across the European Union to support patient access following the approval. The company has already incorporated the expected impact of the authorization into its financial forecast for the fiscal year ending March 31, 2027.
What This Means for Patients
For patients with muscle-invasive bladder cancer who cannot receive cisplatin chemotherapy, this approval provides the first approved treatment option before and after surgery in Europe. The combination of PADCEV and Keytruda has been shown to lower the risk of cancer recurrence and improve survival, offering a new opportunity for better long-term outcomes.
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About the Writer
Kalyani Boharapi (LinkedIn) is a pharmacy professional and healthcare writer currently pursuing an M.Pharm in Regulatory Affairs at Dr. D. Y. Patil College of Pharmacy, with interests in pharmaceutical regulations, drug development, and healthcare innovation. She has academic exposure to dossier preparation, scientific writing, and regulatory documentation. Kalyani has also completed certification courses in Generative AI, AI in Pharma, and Bioinformatics, and actively participates in pharmaceutical conferences to stay updated with emerging trends and advancements in the healthcare and pharmaceutical industry.