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Pfizer Inc. and Astellas Pharma Inc. announced that the US Food and Drug Administration (FDA) has approved Padcev (enfortumab vedotin-ejfv), a Nectin-4 directed antibody-drug conjugate, plus the PD-1 inhibitor, Keytruda (pembrolizumab) or Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) as neoadjuvant and adjuvant (before and after surgery) treatment for adult patients with muscle-invasive bladder cancer regardless of cisplatin eligibility. This now marks the first platinum-free regimen approved for adult patients with MIBC, regardless of cisplatin eligibility.
The approval was based on results from the pivotal phase 3 EV-304 clinical trial (also known as KEYNOTE-B15), which were presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU). This expanded indication builds on the November 2025 US FDA approval of the combination for use as neoadjuvant and adjuvant treatment in cisplatin-ineligible adult patients with MIBC, based on results from the EV-303 phase 3 clinical trial (also known as KEYNOTE-905) that were published in the New England Journal of Medicine.
Christopher Hoimes, DO, director of the Bladder Cancer Programme and Center for Cancer Immunotherapy at Duke Cancer Institute, and an EV-304 Principal Investigator, said: “For muscle-invasive bladder cancer, a comprehensive treatment approach is important; the neoadjuvant phase can help shrink the tumour and target undetectable cancer cells early before surgery, while the adjuvant phase can be critical in eliminating residual, undetectable cancer cells following surgery. These data from EV-304 and this approval show 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 for adult patients with muscle-invasive bladder cancer.”
Aamir Malik, executive vice president, chief US commercial officer, Pfizer, said: “Today’s approval marks a historic turning point for the treatment of muscle-invasive bladder cancer, providing adult patients with the first approved platinum-free combination regimen shown to significantly improve survival over the current standard of care – regardless of cisplatin-eligibility. Padcev plus pembrolizumab has established itself as the standard of care for first line therapy of advanced stages of bladder cancer, and we’re thrilled to be able to provide this community a much-needed new treatment option in an earlier, potentially curative-intent setting.”
Moitreyee Chatterjee-Kishore, PhD, MBA, head of oncology development, Astellas, said: “The approval of neoadjuvant and adjuvant Padcev plus pembrolizumab expands the established impact of this combination and represents a critical leap forward in how muscle-invasive bladder cancer can be treated. By delivering a clinically meaningful survival benefit, with profound event-free survival and pathological complete response rates, this regimen is the first platinum-free treatment option in nearly 25 years to outperform standard of care chemotherapy, offering new hope to patients living with this disease.”
In the EV-304 clinical trial, patients were randomized to receive surgery with neoadjuvant and adjuvant Padcev plus pembrolizumab or surgery with neoadjuvant chemotherapy. Padcev plus pembrolizumab was administered as a planned total of 9 cycles of Padcev and 17 cycles of pembrolizumab split before and after surgery. Padcev plus pembrolizumab demonstrated:
• A 47% reduction in the risk of tumour recurrence, progression or death compared to patients treated with standard of care neoadjuvant gemcitabine and cisplatin (Hazard Ratio (HR) of 0.53; 95% Confidence Interval (CI), 0.41–0.70; 1-sided p<0.0001).
• An estimated 79.4% of patients were event-free at two years, compared with 66.2% treated with standard of care.
• A 35% reduction in the risk of death compared to neoadjuvant chemotherapy (HR of 0.65; 95% CI, 0.48-0.89; 1-sided p=0.0029).
• A pathological complete response (pCR) rate of 55.8% compared with 32.5% with chemotherapy at the time of surgery (estimated difference 23.4%; 95% CI 16.7-29.8; 1-sided p<0.0001).
• A safety profile consistent with prior experience with this combination, and no new identifiable safety signals. Grade =3 adverse events (AEs) due to any cause occurred in 75.7% of patients treated with neoadjuvant and adjuvant Padcev plus pembrolizumab compared to 67.2% of patients treated with neoadjuvant chemotherapy.
The EV-304 trial is an ongoing, open-label, randomized, controlled, phase 3 study evaluating neoadjuvant and adjuvant enfortumab vedotin in combination with pembrolizumab versus neoadjuvant chemotherapy (gemcitabine and cisplatin) in patients with MIBC who are eligible for cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant (before and after surgery) enfortumab vedotin in combination with pembrolizumab (arm A) or neoadjuvant gemcitabine-cisplatin chemotherapy (arm B). Curative-intent surgery (cystectomy) was performed in both arms. Enfortumab vedotin in combination with pembrolizumab was administered as a planned total of 9 cycles of enfortumab vedotin and 17 cycles of pembrolizumab split before and after surgery.
The primary endpoint of this trial is EFS, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) or failure to undergo RC in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence based on blinded independent central review (BICR) or death due to any cause. Key secondary endpoints include OS and pCR rate.
Bladder cancer is the ninth most common cancer worldwide, diagnosed in more than 614,000 people each year globally, including an estimated 85,000 people in the US. MIBC represents approximately 30% of all bladder cancer cases. The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery. Even after undergoing surgery to have their bladder removed, approximately half of patients with MIBC experience disease recurrence.
Padcev (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. Nonclinical data suggest the anticancer activity of Padcev is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumour agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).
Padcev plus pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph is approved for the treatment of adult patients with MIBC in the United States and for cisplatin-ineligible patients with MIBC in the European Union.
Padcev plus pembrolizumab is also approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) in the United States, the European Union, Japan and a number of other countries around the world. Padcev is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
Boxed warning: Serious skin reactions:
• Padcev (enfortumab vedotin-ejfv) can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
• Closely monitor patients for skin reactions.
• Immediately withhold Padcev and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
• Permanently discontinue Padcev in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Padcev, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, as neoadjuvant treatment and then continued after cystectomy as adjuvant treatment, is indicated for the treatment of adult patients with muscle invasive bladder cancer (MIBC).
Padcev, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC).
Padcev, as a single agent, is indicated for the treatment of adult patients with la/mUC who:
• have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
• are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
Seagen and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seagen’s and Astellas’ Padcev (enfortumab vedotin-ejfv) and Merck’s Keytruda (pembrolizumab) in patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy. Pfizer Inc. successfully completed its acquisition of Seagen on December 14, 2023. Keytruda is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).
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