Pfizer and Astellas Announce Landmark Phase 3 Results for PADCEV™ Plus KEYTRUDA™ in Muscle-Invasive Bladder Cancer, Marking Potential Paradigm Shift in Treatment for Cisplatin-Ineligible Patients
Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura) have unveiled promising new clinical data that could redefine treatment standards for a high-risk bladder cancer population with few effective options. The companies announced positive topline results from the Phase 3 EV-303 clinical trial—also known as KEYNOTE-905—evaluating PADCEV™ (enfortumab vedotin), an innovative Nectin-4 directed antibody-drug conjugate, in combination with KEYTRUDA™ (pembrolizumab), a PD-1 immune checkpoint inhibitor, as both neoadjuvant (before surgery) and adjuvant (after surgery) therapy for patients with muscle-invasive bladder cancer (MIBC) who are not eligible for, or decline, standard cisplatin-based chemotherapy.
A Breakthrough in a Historically Challenging Setting
For decades, patients with MIBC who could not receive cisplatin—the most effective chemotherapy agent in this setting—have faced bleak outcomes. Standard care for cisplatin-ineligible patients has been limited to surgery alone, a treatment path associated with high recurrence rates and limited survival gains. While bladder removal (radical cystectomy) can be curative in some cases, many patients experience local or distant relapse, and there have been no major systemic therapy advances for this subgroup in decades.
The EV-303 trial now offers a hopeful alternative.
At the first interim efficacy analysis, the combination of PADCEV plus KEYTRUDA delivered a clinically meaningful and statistically significant improvement in both event-free survival (EFS)—the primary endpoint of the study—and overall survival (OS), a key secondary endpoint, when compared with surgery alone. The study also met an additional secondary endpoint of pathologic complete response (pCR) rate, indicating a higher proportion of patients whose tumors were completely eradicated in surgical specimens after neoadjuvant treatment.
Expert Perspective on the Significance
“Patients with muscle-invasive bladder cancer who are ineligible for cisplatin treatment have not seen a significant treatment advance in decades and face high rates of disease recurrence and a poor prognosis, even after having their bladder removed,”
said Christof Vulsteke, M.D., Ph.D., Head of Integrated Cancer Center Ghent (IKG, Belgium) and Clinical Trial Unit Oncology Ghent, and principal investigator for EV-303.
“These results mark the first time a systemic treatment approach, used before and after surgery, has significantly extended survival over surgery alone in this population. This demonstrates the potential of this combination to address a critical unmet patient need.”
The trial will continue to collect and mature data on the secondary EFS, OS, and pCR endpoints for the arm evaluating neoadjuvant and adjuvant KEYTRUDA monotherapy versus surgery alone. Importantly, the safety profiles for both PADCEV plus KEYTRUDA and KEYTRUDA alone were consistent with what has been previously observed for these drugs in other clinical contexts—suggesting no unexpected toxicity concerns emerged in the perioperative setting.
Astellas and Pfizer Leaders on the Data
Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Head of Oncology Development at Astellas, described the results as potentially transformative:
“These results from EV-303 represent a breakthrough for cisplatin-ineligible patients with muscle-invasive bladder cancer, demonstrating the potential of PADCEV in combination with KEYTRUDA when used before and after surgery as a new standard of care. We look forward to presenting further details on these data at an upcoming medical congress.”
From Pfizer’s perspective, this builds on prior success with the PADCEV plus KEYTRUDA regimen in advanced urothelial carcinoma:
“PADCEV plus KEYTRUDA has already changed the treatment paradigm for patients with locally advanced or metastatic urothelial cancer as standard of care,” said Johanna Bendell, M.D., Oncology Chief Development Officer at Pfizer.
“These latest results underscore the practice-changing potential of this combination in earlier stages of bladder cancer, where it has the potential to improve outcomes for even more patients. We are deeply grateful to the patients and investigators who made this trial possible.”
Understanding Muscle-Invasive Bladder Cancer and the Need for Innovation
Bladder cancer ranks as the ninth most common cancer worldwide, with more than 614,000 cases diagnosed annually. While the majority of bladder cancers are diagnosed at early stages and are non-muscle-invasive, about 30% of cases present as MIBC—a more aggressive form in which the cancer has penetrated into the muscle layer of the bladder wall.
Historically, the best chance for cure has been neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. This approach improves survival and reduces recurrence risk. Unfortunately, up to 50% of MIBC patients are ineligible for cisplatin due to factors such as impaired kidney function, poor performance status, hearing loss, or other comorbidities. For these patients, the treatment pathway has been surgery alone, leaving a significant gap in outcomes compared to those able to receive chemotherapy.
EV-303 addresses this gap by offering a novel, immune-enhancing, targeted approach that can be applied even in the absence of cisplatin.
About PADCEV™ (enfortumab vedotin)
PADCEV is an antibody-drug conjugate (ADC) that targets Nectin-4, a protein highly expressed in urothelial cancer cells but minimally present in normal tissue. Once bound to Nectin-4, PADCEV delivers a cell-killing agent directly into the tumor cell, causing targeted destruction while minimizing damage to healthy cells. PADCEV has already secured regulatory approvals in multiple regions for the treatment of advanced or metastatic urothelial cancer, both as monotherapy and in combination with KEYTRUDA.
About KEYTRUDA™ (pembrolizumab)
KEYTRUDA is a monoclonal antibody that blocks the PD-1 checkpoint pathway, effectively releasing the “brakes” on the immune system and enabling T-cells to recognize and destroy cancer cells. It is one of the most widely studied cancer immunotherapies and is approved across a broad range of tumor types, including advanced urothelial carcinoma. The rationale for combining KEYTRUDA with PADCEV is to simultaneously attack the tumor through direct cytotoxicity and immune system activation, potentially achieving more durable responses.
Details of the EV-303 / KEYNOTE-905 Trial
The EV-303 trial is an ongoing, open-label, randomized, three-arm, controlled Phase 3 study. Its aim is to evaluate the safety and efficacy of:
- Arm A: Neoadjuvant and adjuvant KEYTRUDA monotherapy
- Arm B: Surgery alone (radical cystectomy, standard of care for cisplatin-ineligible patients)
- Arm C: Neoadjuvant and adjuvant PADCEV plus KEYTRUDA combination therapy
All participants enrolled in the study were either ineligible for or declined cisplatin-based chemotherapy.
Endpoints and Definitions
- Primary Endpoint: Event-Free Survival (EFS) between Arm C and Arm B.
- EFS is defined as the time from randomization to any of the following: disease progression that prevents surgery, failure to undergo surgery in patients with residual disease, gross residual disease left after surgery, local or distant recurrence (as shown on imaging or biopsy), or death from any cause.
- Key Secondary Endpoints:
- Overall Survival (OS)
- Pathologic Complete Response (pCR) rate (absence of invasive cancer in bladder and lymph nodes after neoadjuvant therapy)
- Comparative analyses between Arm A vs. Arm B and Arm C vs. Arm B for EFS, OS, and pCR
More information on the EV-303 study can be found on clinicaltrials.gov.
Next Steps and Regulatory Pathway
Pfizer and Astellas plan to present detailed efficacy and safety results at an upcoming major medical congress in oncology. They will also engage with regulatory authorities globally to discuss potential filings for approval of PADCEV plus KEYTRUDA in the perioperative setting for cisplatin-ineligible MIBC patients.
In parallel, the combination is being studied in cisplatin-eligible MIBC patients through the EV-304 Phase 3 trial (also known as KEYNOTE-B15), which could further broaden the eligible population for this regimen.
A Potential New Standard of Care
If approved, PADCEV plus KEYTRUDA could become the first systemic therapy combination proven to extend survival in cisplatin-ineligible MIBC patients when given both before and after surgery. This would represent not only a therapeutic milestone for bladder cancer but also a significant expansion of the role for ADC–immunotherapy combinations in earlier-stage solid tumors.
As Dr. Vulsteke emphasized, “This is the first time we’re seeing a systemic therapy meaningfully change the trajectory for these patients, who have long faced limited hope beyond surgery.”
The results also underscore a broader trend in oncology: moving effective metastatic treatments into earlier disease settings to maximize curative potential. With this shift, more patients may benefit from innovative therapies before their disease progresses beyond the point of surgical control.
