Key Takeaways:
The U.S. Food and Drug Administration approved Pfizer Inc. and Astellas Pharma Inc.'s Padcev (enfortumab vedotin) plus Merck's Keytruda (pembrolizumab) as neoadjuvant and adjuvant treatment for all surgery-eligible adults with muscle-invasive bladder cancer, regardless of cisplatin eligibility.
The regimen cut the risk of tumor recurrence, progression or death by 47% compared with standard-of-care gemcitabine and cisplatin chemotherapy, according to data from the Phase 3 EV-304 trial (also known as KEYNOTE-B15). The hazard ratio of 0.53 (95% CI, 0.41-0.70; p<0.0001) means patients receiving the combination had a 47% lower risk of those events at any given time versus chemotherapy.
"This approval shows that by delivering this regimen across both the neoadjuvant and adjuvant phases, without platinum-based chemotherapy, we can significantly reduce the risk of recurrence and improve overall survival — offering a potential new standard of care," Christopher Hoimes, director of the Bladder Cancer Program at Duke Cancer Institute and an EV-304 principal investigator, said.
The combination also demonstrated a 35% reduction in the risk of death versus neoadjuvant chemotherapy (HR 0.65; 95% CI, 0.48-0.89; p=0.0029). At the time of surgery, 55.8% of patients receiving Padcev plus Keytruda achieved a pathological complete response — meaning no detectable cancer cells remained in the surgical specimen — compared with 32.5% in the chemotherapy arm. An estimated 79.4% of patients in the combination arm were event-free at two years, versus 66.2% with standard of care.
The expanded approval builds on a November 2025 FDA clearance limited to cisplatin-ineligible patients, which was based on the EV-303 trial. The EV-304 trial enrolled 808 patients with previously untreated MIBC who were eligible for cisplatin-based chemotherapy and candidates for radical cystectomy. Patients received either four cycles of neoadjuvant Padcev plus Keytruda before surgery followed by five additional cycles of Padcev and continued Keytruda afterward, or standard neoadjuvant gemcitabine-cisplatin followed by surgery.
Grade 3 or higher adverse events from any cause occurred in 75.7% of patients receiving the combination versus 67.2% receiving chemotherapy. The safety profile was consistent with prior experience, with no new identifiable signals. Padcev carries a boxed warning for severe and fatal skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Bladder cancer is the ninth most common cancer worldwide, with more than 614,000 new cases diagnosed annually, including about 85,000 in the U.S. MIBC accounts for roughly 30% of all bladder cancer cases. Even after bladder removal surgery, about half of patients experience disease recurrence.
The approval marks the first platinum-free regimen cleared for MIBC regardless of cisplatin eligibility in nearly 25 years. Padcev plus Keytruda is already established as a standard of care for first-line treatment of advanced-stage bladder cancer. The expanded label opens a potentially curative-intent setting to a broader patient population. Pfizer and Astellas will now seek regulatory approvals in other markets, including the European Union, where the combination is already approved for cisplatin-ineligible MIBC.
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