Pfizer Inc. and Astellas Pharma Inc., led by President and CEO Naoki Okamura, announced that the U.S. Food and Drug Administration has approved PADCEV (enfortumab vedotin-ejfv) in combination with the PD-1 inhibitor Keytruda or Keytruda QLEX as a neoadjuvant treatment before cystectomy and continued afterward as adjuvant therapy for adults with muscle-invasive bladder cancer who cannot receive cisplatin-based chemotherapy. This approval is based on data from the Phase 3 EV-303 study, also called KEYNOTE-905, which was presented at the European Society of Medical Oncology Congress in 2025.
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Dr. Matthew Galsky, Lillian and Howard Stratton Professor of Medicine and Director of Genitourinary Medical Oncology at Mount Sinai Tisch Cancer Center, and an EV-303 investigator, said that combining enfortumab vedotin with pembrolizumab addresses a critical unmet need. He highlighted that many patients with muscle-invasive bladder cancer face cancer recurrence even after surgery, and those ineligible for cisplatin had limited options for decades. This new treatment showed significant improvements in both event-free and overall survival, offering a potentially practice-changing approach for these patients.
Jeff Legos, PhD, MBA, Chief Oncology Officer at Pfizer, noted that the FDA approval arrived ahead of schedule and marks a new era for patients with cisplatin-ineligible bladder cancer. He emphasized that PADCEV plus pembrolizumab is the first perioperative treatment to demonstrate a clear survival benefit compared to surgery alone, providing new hope for patients and families.
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In the EV-303 trial, patients receiving PADCEV plus pembrolizumab had a 60 percent reduction in the risk of tumor recurrence, progression, or death compared to surgery alone. The probability of remaining event free at the study time point was 74.7 percent for the combination group versus 39.4 percent for the surgery-only group. Median event-free survival has not been reached for the combination group, while it was 15.7 months for surgery alone. Overall survival analysis showed a 50 percent reduction in the risk of death for patients receiving the combination, with two-year survival rates of 79.7 percent versus 63.1 percent for surgery only. Median overall survival has not yet been reached for the combination therapy, compared to 41.7 months in the surgery arm.
Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development at Astellas, highlighted that PADCEV plus pembrolizumab has already become a standard of care in locally advanced or metastatic urothelial cancer. This new approval extends the combination to an earlier disease stage for cisplatin-ineligible patients, positioning it as the only antibody-drug conjugate and PD-1 inhibitor regimen approved for this population. She emphasized that the approval demonstrates Astellas’ commitment to expanding access to this innovative therapy.
Safety results from EV-303 were consistent with prior studies of the combination. The most common adverse reactions included increased glucose, decreased hemoglobin, liver enzyme elevations, rash, fatigue, pruritus, peripheral neuropathy, alopecia, gastrointestinal issues, urinary tract infections, dry eye, and weight loss. Severe adverse events of grade three or higher occurred in 71.3 percent of patients on the combination and 45.9 percent in the surgery-only group.
The EV-303 trial is an ongoing, open-label, randomized Phase 3 study evaluating neoadjuvant and adjuvant PADCEV with pembrolizumab, neoadjuvant and adjuvant pembrolizumab alone, and surgery alone in patients with muscle-invasive bladder cancer who are ineligible for cisplatin or declined it. The trial’s primary endpoint is event-free survival comparing PADCEV plus pembrolizumab to surgery alone. Key secondary endpoints include overall survival and pathologic complete response rates across treatment arms. The study is designed to assess whether perioperative therapy with PADCEV plus pembrolizumab can improve long-term outcomes and reduce recurrence risk for these patients.
This approval offers a new, evidence-based option for patients who previously had limited treatment choices and could reshape the standard of care for muscle-invasive bladder cancer.
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