FDA Authorizes PADCEV® + Keytruda® Regimen for Eligible Individuals with Bladder Cancer
Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503; President and CEO: Naoki Okamura, “Astellas”) announced that the U.S. Food and Drug Administration (FDA) has approved PADCEV® (enfortumab vedotin-ejfv), a Nectin-4–directed antibody-drug conjugate (ADC), in combination with the PD-1 inhibitor Keytruda® (pembrolizumab) or the newly approved Keytruda QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph). The combination is now authorized as a perioperative treatment—meaning it is administered both before and after surgery—for adult patients with muscle-invasive bladder cancer (MIBC) who are not eligible for cisplatin-containing chemotherapy. The regimen is approved for use as neoadjuvant therapy ahead of cystectomy (bladder removal surgery), followed by continued administration in the adjuvant setting after surgery.¹
This landmark approval is supported by data from the pivotal Phase 3 EV-303 clinical trial (also known as KEYNOTE-905), which was featured during a Presidential Symposium at the European Society of Medical Oncology (ESMO) Congress 2025. As the first perioperative regimen demonstrating a clear and meaningful survival benefit over standard surgery alone in cisplatin-ineligible patients, the combination of PADCEV and pembrolizumab represents a major therapeutic advancement for a patient population that has historically had very limited treatment options.
A Major Shift for Muscle-Invasive Bladder Cancer Patients
Muscle-invasive bladder cancer remains one of the most challenging urologic malignancies to treat. Even after radical cystectomy—one of the most aggressive surgical treatments in oncology—roughly half of all patients experience disease recurrence. Despite this high risk, a substantial proportion of patients cannot receive cisplatin-based chemotherapy due to kidney dysfunction, poor performance status, neuropathy, or other underlying health issues. For decades, this gap in effective perioperative treatments has left physicians with few tools to reduce recurrence risk in these patients.
Dr. Matthew Galsky, Lillian and Howard Stratton Professor of Medicine and Director of Genitourinary Medical Oncology at the Mount Sinai Tisch Cancer Center, and an investigator on EV-303, underscored the significance of the approval.
“Enfortumab vedotin plus pembrolizumab is poised to address a critical unmet need. Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin. This approval, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades.”
Regimen Granted Early Approval Based on Transformative Outcomes
The FDA’s decision to approve the combination several months ahead of its original regulatory review timeline highlights the clear magnitude of benefit observed in the EV-303 study.
Jeff Legos, PhD, MBA, Chief Oncology Officer at Pfizer, noted the importance of this accelerated timeline:
“Today’s approval, granted months earlier than anticipated, ushers in a new era of treatment for cisplatin-ineligible patients with MIBC who have long been underserved by existing treatments. PADCEV plus pembrolizumab is the first and only FDA-approved perioperative treatment regimen to demonstrate a meaningful survival advantage compared to surgery alone, positioning it to reshape the treatment landscape and bring new hope to patients and families.”
EV-303 / KEYNOTE-905: Strong Survival Benefits in the Perioperative Setting
Results from EV-303 revealed compelling improvements in both event-free survival (EFS) and overall survival (OS), the two most clinically relevant measures of long-term benefit in the perioperative setting.
Event-Free Survival
Perioperative treatment with PADCEV plus pembrolizumab achieved:
- A 60% reduction in the risk of tumor recurrence, disease progression, or death compared to surgery alone (Hazard Ratio [HR] = 0.40; 95% CI: 0.28–0.57; p < 0.0001).
- An event-free probability of 74.7% in the combination arm versus 39.4% in the surgery-only arm.
- The estimated median EFS was not reached in the combination group, while the surgery-alone group demonstrated a median EFS of 15.7 months, underscoring the consistency and durability of the treatment effect.²
Overall Survival
The key secondary endpoint, overall survival, further demonstrated the significant impact of adding PADCEV and pembrolizumab:
- A 50% reduction in the risk of death compared to surgery alone (HR = 0.50; 95% CI: 0.33–0.74; p = 0.0002).
- Two-year survival probability of 79.7% for the combination regimen versus 63.1% for surgery alone.
- As with EFS, the median OS has not yet been reached for patients treated with the combination, compared with 41.7 months for the surgery-only group.²
These results collectively support a powerful and sustained clinical benefit, making PADCEV plus pembrolizumab the new benchmark of care for cisplatin-ineligible patients with MIBC.
Astellas: Expanding the Role of an Established Combination Therapy
The approval reflects the long-term development strategy behind PADCEV in combination with pembrolizumab, which is already recognized as a foundational therapy for locally advanced or metastatic urothelial cancer.
Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development at Astellas, emphasized the broader implications:
“Building on the combination’s established role in locally advanced or metastatic urothelial cancer, where it has become standard of care in the U.S., PADCEV plus pembrolizumab now has the potential to redefine care in an earlier disease setting as the only antibody-drug conjugate and PD-1 inhibitor regimen for cisplatin-ineligible patients with MIBC. The approval underscores our unwavering commitment to expanding the reach of this innovative combination to more eligible patients with bladder cancer.”
Safety Profile and Tolerability
The safety results observed in the EV-303 study were consistent with previously reported safety profiles for this combination, and no new safety signals were identified. Among patients treated with PADCEV plus intravenous pembrolizumab, the most common (≥20%) adverse reactions—also incorporating laboratory abnormalities—included:
- Increased glucose
- Decreased hemoglobin
- Elevated AST
- Rash
- Elevated ALT
- Fatigue
- Pruritus
- Increased creatinine
- Hyponatremia
- Decreased lymphocytes
- Peripheral neuropathy
- Hyperkalemia
- Alopecia
- Dysgeusia
- Diarrhea
- Decreased appetite
- Constipation
- Nausea
- Hypophosphatemia
- Urinary tract infection
- Dry eye
- Weight loss
Grade ≥3 adverse events occurred in 71.3% of combination-arm patients compared with 45.9% of those in the surgery-only arm.² These findings align with the known safety profile of enfortumab vedotin and pembrolizumab, particularly relating to peripheral neuropathy, skin reactions, and metabolic changes.
Due to the ADC’s mechanism of action, PADCEV carries a boxed warning for serious and potentially life-threatening adverse reactions, which physicians must monitor carefully. Detailed Important Safety Information is provided at the end of the original announcement.
Ongoing Expansion of the Clinical Program
In addition to the newly approved use in cisplatin-ineligible patients, the PADCEV plus pembrolizumab combination is being actively investigated in the EV-304 Phase 3 trial (KEYNOTE-B15). This companion study evaluates the same perioperative regimen in cisplatin-eligible patients with muscle-invasive bladder cancer. If successful, this trial could further broaden the combination’s use to encompass nearly the entire population of patients undergoing surgery for MIBC.
A New Standard of Care for Cisplatin-Ineligible Muscle-Invasive Bladder Cancer
The FDA’s approval of perioperative PADCEV plus pembrolizumab marks one of the most significant advancements in bladder cancer treatment in decades. For a long-neglected patient population—those unable to receive cisplatin—the combination now provides a robust, evidence-based option that improves both event-free and overall survival.
By moving an effective metastatic regimen into the earlier stages of disease, Pfizer and Astellas have introduced a potentially practice-changing therapeutic approach that could alter the natural course of muscle-invasive bladder cancer. As additional data mature and further clinical trials read out, the role of antibody–drug conjugates paired with checkpoint inhibitors may continue to expand, offering renewed hope for improved outcomes in this aggressive malignancy.
About the EV-303/KEYNOTE-905 Trial
The EV-303 trial (also known as KEYNOTE-905) is an ongoing, open-label, randomized, three-arm, controlled, Phase 3 study evaluating neoadjuvant and adjuvant PADCEV in combination with pembrolizumab or neoadjuvant and adjuvant pembrolizumab versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. Patients were randomized to receive either neoadjuvant and adjuvant pembrolizumab (arm A), surgery alone (arm B) or neoadjuvant and adjuvant PADCEV in combination with pembrolizumab (arm C).iii
The primary endpoint of this trial is EFS between arm C and arm B, defined as time from randomization to the first of: disease progression preventing curative surgery, failure to undergo surgery for participants with muscle invasive residual disease, incomplete surgical resection, local or distant recurrence after surgery, or death.i Key secondary endpoints include OS and pCR rate between arm C and arm B, as well as EFS, OS and pCR rate between arm A and arm B.viii
For more information on the global EV-303 trial, go to clinicaltrials.gov.
About Muscle-Invasive Bladder Cancer
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 U.S.iv,v MIBC represents approximately 30% of all bladder cancer cases.vi The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery, which has been shown to prolong survival.vii However, up to half of patients who are diagnosed with MIBC are not eligible to receive cisplatin and face limited treatment options, typically undergoing surgery without any systemic treatment.viii Of those who do undergo bladder surgery, one third are cisplatin-ineligible.
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