PADCEV plus Keytruda has become the first platinum-free treatment regimen cleared by the U.S. Food and Drug Administration (FDA) for adults with muscle-invasive bladder cancer (MIBC), regardless of whether they can tolerate cisplatin-based chemotherapy. Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503) announced the approval on July 10, 2026, positioning the combination as a potential new standard of care for patients facing surgery for this aggressive form of bladder cancer.
The newly expanded approval allows PADCEV® (enfortumab vedotin-ejfv), a Nectin-4 directed antibody-drug conjugate, to be used alongside the PD-1 inhibitor Keytruda® (pembrolizumab) or Keytruda QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) as both neoadjuvant therapy (before surgery) and adjuvant therapy (after surgery). Unlike the standard-of-care approach, which relies on platinum-based chemotherapy, this regimen removes platinum from the treatment pathway entirely, a shift oncologists have been working toward for decades.
Bladder cancer ranks as the ninth most common cancer diagnosed worldwide, affecting more than 614,000 people globally each year, including roughly 85,000 people in the United States. MIBC accounts for about 30% of all bladder cancer cases, and even after patients undergo surgery to remove the bladder, nearly half experience disease recurrence. That recurrence risk is exactly what the PADCEV plus Keytruda regimen was designed to address.
What the FDA Approval Means for PADCEV Plus Keytruda Patients
This decision builds directly on a November 2025 FDA approval that cleared the same combination for cisplatin-ineligible MIBC patients, based on the EV-303/KEYNOTE-905 trial published in the New England Journal of Medicine. The new approval closes the gap, meaning PADCEV plus Keytruda is now available to essentially the entire adult MIBC population, both cisplatin-eligible and cisplatin-ineligible patients, using a single, platinum-free framework.
The approval rests on results from the pivotal Phase 3 EV-304 trial (also known as KEYNOTE-B15), first presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU). In that trial, patients were randomized to receive either surgery combined with neoadjuvant and adjuvant PADCEV plus pembrolizumab, or surgery combined with standard neoadjuvant gemcitabine-cisplatin chemotherapy. The treatment arm received a planned total of 9 cycles of PADCEV and 17 cycles of pembrolizumab, split across the pre- and post-surgical phases.
Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute and an EV-304 principal investigator, said a comprehensive approach matters for MIBC because the neoadjuvant phase can shrink tumors and target undetectable cancer cells before surgery, while the adjuvant phase helps eliminate residual disease afterward. He noted the EV-304 data show that delivering PADCEV plus Keytruda across both phases, without platinum-based chemotherapy, significantly reduces recurrence risk and improves overall survival.
EV-304 Trial Data Behind the PADCEV Plus Keytruda Approval
The clinical case for PADCEV plus Keytruda is built on measurable, statistically significant outcomes. Compared with standard-of-care neoadjuvant chemotherapy, the combination demonstrated a nearly 50% reduction in the risk of tumor recurrence, progression, or death, along with a 35% reduction in the risk of death in cisplatin-eligible patients. The table below summarizes the key efficacy findings reported by Pfizer and Astellas.
Aamir Malik, Executive Vice President and Chief U.S. Commercial Officer at Pfizer, called the approval a “historic turning point” for MIBC treatment, noting that PADCEV plus Keytruda already established itself as the standard first-line therapy for advanced bladder cancer and now extends into an earlier, potentially curative-intent setting. Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development at Astellas, added that the regimen is the first platinum-free option in nearly 25 years to outperform standard-of-care chemotherapy in this setting.
Safety Profile and Boxed Warning for PADCEV Plus Keytruda
Regulatory approval doesn’t come without caveats, and PADCEV carries a boxed warning for serious skin reactions. The prescribing information warns that PADCEV can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which occur predominantly during the first treatment cycle but may appear later. Physicians are advised to closely monitor patients for skin reactions and to immediately withhold treatment if SJS, TEN, or severe skin reactions are suspected.
In the EV-304 neoadjuvant phase, serious adverse reactions occurred in 27% of the 403 patients treated with PADCEV plus Keytruda, with the most common being rash (3.2%), pneumonitis/interstitial lung disease (2.2%), and diarrhea (1.7%). Fatal adverse reactions occurred in 1.7% of patients. In the adjuvant phase, serious adverse reactions rose to 36%, and adverse reactions led to treatment discontinuation in 16% of patients. Other notable risks associated with PADCEV include hyperglycemia and diabetic ketoacidosis, pneumonitis/interstitial lung disease, peripheral neuropathy, and ocular disorders such as dry eye and blurred vision.
Patients and caregivers considering this regimen should review the full FDA Prescribing Information for PADCEV, including the complete boxed warning, before starting treatment.
The Pfizer, Astellas, and Merck Collaboration Behind PADCEV Plus Keytruda
PADCEV plus Keytruda is the product of a three-way collaboration. Seagen and Astellas originally entered a clinical partnership with Merck to study the combination of PADCEV and Keytruda in MIBC patients eligible for cisplatin-based chemotherapy. Pfizer entered the picture after completing its acquisition of Seagen on December 14, 2023, inheriting PADCEV’s development program. Keytruda remains a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
PADCEV plus pembrolizumab (or pembrolizumab and berahyaluronidase alfa-pmph) is now approved for MIBC treatment in the United States, and for cisplatin-ineligible MIBC patients in the European Union. The combination is also approved for locally advanced or metastatic urothelial cancer in the U.S., EU, Japan, and other countries, while PADCEV as a single agent carries separate approvals for patients who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.
