PADCEV® Combination Approved for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility
Pfizer Inc. and Astellas Pharma Inc. have announced that the U.S. Food and Drug Administration (FDA) has approved PADCEV® (enfortumab vedotin-ejfv) in combination with the PD-1 inhibitor Keytruda® (pembrolizumab) or Keytruda QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph) for the neoadjuvant and adjuvant treatment of adults with muscle-invasive bladder cancer (MIBC), regardless of their eligibility to receive cisplatin-based chemotherapy.
The approval marks a major advancement in bladder cancer treatment by introducing the first platinum-free perioperative regimen approved for patients with muscle-invasive bladder cancer. The expanded indication allows the combination therapy to be administered both before surgery (neoadjuvant treatment) and after surgery (adjuvant treatment), providing a comprehensive treatment strategy designed to reduce disease recurrence and improve long-term survival outcomes.
The FDA’s decision was supported by results from the pivotal Phase 3 EV-304 clinical trial, also known as KEYNOTE-B15, which demonstrated significant improvements in event-free survival, overall survival, and pathological complete response rates compared with the current standard of care based on platinum-containing chemotherapy.
A Significant Milestone in Bladder Cancer Care
Muscle-invasive bladder cancer represents one of the most aggressive forms of bladder cancer.
Unlike non-muscle-invasive disease, MIBC extends beyond the bladder lining into the muscular wall of the bladder, substantially increasing the risk of local progression, recurrence, and distant metastasis.
Standard treatment has traditionally involved a combination of surgery and cisplatin-based chemotherapy.
Patients typically receive chemotherapy before surgery to shrink tumors and eliminate microscopic disease, followed by radical cystectomy and, in selected cases, additional postoperative treatment.
However, many patients are unable to receive cisplatin because of:
- Impaired kidney function
- Hearing loss
- Peripheral neuropathy
- Poor overall physical condition
- Other medical comorbidities
The availability of a platinum-free treatment option regardless of cisplatin eligibility addresses a long-standing unmet need within bladder cancer care.
Building Upon Earlier FDA Approval
The latest approval expands upon a previous FDA authorization granted in November 2025.
At that time, PADCEV plus pembrolizumab received approval for cisplatin-ineligible adults with muscle-invasive bladder cancer, based on findings from the EV-303 (KEYNOTE-905) Phase 3 clinical trial.
Results from EV-303 were subsequently published in the New England Journal of Medicine, demonstrating the potential of combining an antibody-drug conjugate with immunotherapy in earlier-stage bladder cancer.
The new approval extends use of the combination to all eligible adults with muscle-invasive bladder cancer, eliminating restrictions based on cisplatin eligibility.
The EV-304 Clinical Trial
The FDA’s expanded approval was primarily supported by data from the EV-304 (KEYNOTE-B15) Phase 3 study.
The international randomized trial evaluated adults with muscle-invasive bladder cancer undergoing surgery with curative intent.
Participants were assigned to one of two treatment strategies:
- Surgery combined with neoadjuvant and adjuvant PADCEV plus pembrolizumab.
- Surgery following standard neoadjuvant chemotherapy with gemcitabine and cisplatin.
Patients receiving the investigational regimen completed:
- Nine planned cycles of PADCEV
- Seventeen planned cycles of pembrolizumab
Treatment was divided between the preoperative and postoperative periods to maximize disease control throughout the patient’s surgical journey.
Strong Improvement in Event-Free Survival
One of the trial’s primary objectives was evaluating event-free survival (EFS).
Event-free survival measures the length of time during which patients remain free from disease recurrence, progression, or death.
The study demonstrated a 47% reduction in the risk of recurrence, progression, or death among patients treated with PADCEV plus pembrolizumab compared with those receiving standard neoadjuvant chemotherapy.
The treatment achieved:
- Hazard Ratio (HR): 0.53
- 95% Confidence Interval: 0.41–0.70
- Highly statistically significant results
At two years:
- 79.4% of patients receiving PADCEV plus pembrolizumab remained event-free.
- 66.2% of patients receiving standard chemotherapy remained event-free.
These findings indicate substantially improved disease control following surgery.
Improvement in Overall Survival
The investigational regimen also demonstrated a statistically significant improvement in overall survival.
Compared with standard chemotherapy, PADCEV plus pembrolizumab reduced the risk of death by 35%.
The reported findings included:
- Hazard Ratio: 0.65
- 95% Confidence Interval: 0.48–0.89
Improved overall survival represents one of the most meaningful clinical endpoints in oncology because it directly reflects patients living longer following treatment.
The survival benefit further strengthens the clinical importance of the combination regimen.
Higher Pathological Complete Response Rates
Another important outcome evaluated during EV-304 was pathological complete response (pCR).
A pathological complete response occurs when no detectable cancer remains in tissue removed during surgery following neoadjuvant treatment.
Patients receiving PADCEV plus pembrolizumab achieved a 55.8% pathological complete response rate.
By comparison:
- Standard chemotherapy produced a pCR rate of 32.5%.
The absolute improvement exceeded 23 percentage points, representing a substantial increase in complete tumor eradication before surgery.
Higher pathological complete response rates have often been associated with improved long-term outcomes in multiple cancer types.
Safety Profile Remained Consistent
Investigators reported that the safety findings observed during EV-304 were generally consistent with previously established experience using PADCEV together with pembrolizumab.
Importantly:
- No new safety signals were identified.
- Adverse events were consistent with known toxicities.
Grade 3 or higher adverse events occurred in:
- 75.7% of patients receiving PADCEV plus pembrolizumab.
- 67.2% of patients receiving standard chemotherapy.
Although severe adverse events were relatively common in both treatment groups, the overall safety profile remained manageable and aligned with previous clinical experience.
Expert Perspective
Dr. Christopher Hoimes, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute and a principal investigator for EV-304, emphasized the importance of treating muscle-invasive bladder cancer throughout both the preoperative and postoperative periods.
According to Dr. Hoimes, neoadjuvant therapy helps shrink tumors while targeting microscopic cancer cells before surgery.
Following surgery, adjuvant therapy may eliminate remaining cancer cells that are not detectable through imaging or pathology.
He noted that EV-304 demonstrated how administering PADCEV plus pembrolizumab across both treatment phases significantly reduced recurrence risk while improving survival without relying on platinum-based chemotherapy.
The findings, he suggested, may establish a new standard of care for adults with muscle-invasive bladder cancer.
Pfizer Highlights Historic Approval
Aamir Malik, Executive Vice President and Chief U.S. Commercial Officer at Pfizer, described the FDA decision as a historic milestone for patients diagnosed with muscle-invasive bladder cancer.
He noted that PADCEV plus pembrolizumab has already become an established treatment option for advanced bladder cancer in the first-line metastatic setting.
The expanded approval now allows physicians to introduce the combination much earlier during treatment when the goal is potentially curative rather than palliative.
According to Malik, offering a platinum-free regimen capable of significantly improving survival regardless of cisplatin eligibility addresses a major unmet medical need.
Astellas Emphasizes Expanded Impact
Dr. Moitreyee Chatterjee-Kishore, Head of Oncology Development at Astellas, highlighted the broader implications of the approval.
She noted that extending use of PADCEV plus pembrolizumab into the perioperative setting represents an important evolution in bladder cancer treatment.
According to Chatterjee-Kishore, the regimen demonstrated meaningful improvements across several clinically important endpoints, including:
- Overall survival
- Event-free survival
- Pathological complete response
She also emphasized that the therapy becomes the first platinum-free treatment in nearly 25 years to outperform the long-standing chemotherapy standard in muscle-invasive bladder cancer.
Understanding PADCEV
PADCEV (enfortumab vedotin-ejfv) is an antibody-drug conjugate (ADC) designed to target Nectin-4, a protein highly expressed on many bladder cancer cells.
The therapy combines:
- A monoclonal antibody that specifically recognizes Nectin-4.
- A potent cytotoxic agent delivered directly to cancer cells.
After binding to tumor cells, the ADC is internalized, releasing its chemotherapy payload inside malignant cells while limiting exposure to surrounding healthy tissue.
Combining PADCEV with pembrolizumab, an immune checkpoint inhibitor targeting PD-1, provides complementary mechanisms of action that both directly attack cancer cells and enhance immune-mediated anti-tumor activity.
The FDA approval of PADCEV plus pembrolizumab as neoadjuvant and adjuvant therapy represents a significant advance in the treatment of muscle-invasive bladder cancer. By becoming the first platinum-free perioperative regimen approved regardless of cisplatin eligibility, the combination offers physicians a new treatment strategy capable of improving event-free survival, overall survival, and pathological complete response rates while expanding options for a broader patient population.
Supported by robust Phase 3 clinical evidence from the EV-304 trial, the approval further strengthens the role of antibody-drug conjugates combined with immunotherapy in earlier stages of cancer treatment. For Pfizer and Astellas, the expanded indication builds upon the growing clinical success of PADCEV plus pembrolizumab across bladder cancer settings, while offering new hope for patients seeking more effective therapies with curative intent before and after surgery.
About the EV-304/KEYNOTE-B15 Trial
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.ii
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.iii
For more information on the global EV-304 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.iii,iv MIBC represents approximately 30% of all bladder cancer cases.v The standard treatment for patients with MIBC is neoadjuvant cisplatin-based chemotherapy followed by surgery.vi Even after undergoing surgery to have their bladder removed, approximately half of patients with MIBC experience disease recurrence.vii
About PADCEV®(enfortumab vedotin-ejfv)
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.viii 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-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).i
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.