PADCEV™ (enfortumab vedotin) plus Keytruda® (pembrolizumab) demonstrated positive topline results in an interim analysis of the Phase 3 EV-304 trial (also known as KEYNOTE-B15), as announced on December 17, 2025, by Astellas Pharma Inc. and Pfizer Inc. The study evaluated the combination as perioperative therapy—administered before and after surgery—in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC).
In the randomized study, perioperative PADCEV plus pembrolizumab was compared with standard-of-care neoadjuvant gemcitabine + cisplatin. The trial met its primary endpoint, demonstrating clinically meaningful and statistically significant improvement in event-free survival (EFS). The combination also showed a statistically significant overall survival (OS) benefit, reported as a key secondary endpoint. In addition, the pathologic complete response (pCR) endpoint for neoadjuvant PADCEV plus pembrolizumab versus neoadjuvant chemotherapy was met, with a clinically meaningful and statistically significant improvement observed. The companies stated that the safety profile was consistent with the known profile of the regimen.
“Despite available treatment options, nearly half of patients with muscle-invasive bladder cancer progress to metastatic disease within three years of diagnosis. The EV-304 results represent a key milestone in the new era of urothelial cancer treatment. Together, the EV-303 and EV-304 results show that perioperative enfortumab vedotin plus pembrolizumab can positively impact the treatment journey for patients with muscle-invasive bladder cancer, offering significant survival gains across cisplatin-ineligible and cisplatin-eligible patients, signaling a shift from conventional platinum-based chemotherapy and the potential to transform the standard of care.”
Christopher Hoimes, DO, Director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute, an EV-304 Principal Investigator said
How does enfortumab vedotin work?
Enfortumab vedotin is an antibody–drug conjugate (ADC) designed to deliver chemotherapy directly to cancer cells while limiting exposure to normal tissues. It consists of a monoclonal antibody linked to a highly potent cytotoxic agent.
The antibody component selectively binds to Nectin-4, a cell-surface protein that is highly expressed in urothelial carcinoma. After binding to Nectin-4 on the tumor cell, the drug–antibody complex is internalized into the cell. Inside the cell, enfortumab vedotin releases its chemotherapy payload, monomethyl auristatin E (MMAE).
MMAE disrupts microtubules, which are essential for cell division, leading to cell-cycle arrest and ultimately programmed cell death. By specifically targeting Nectin-4–expressing tumor cells, enfortumab vedotin concentrates its anti-cancer activity where it is needed most, helping to reduce damage to healthy tissues compared with conventional chemotherapy. This targeted mechanism underpins its clinical activity in advanced and high-risk bladder cancer, particularly in patients with limited treatment options.
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EV-304 (KEYNOTE-B15): trial design and endpoints
EV-304 is an ongoing, open-label, randomized, controlled Phase 3 trial in which patients with muscle-invasive bladder cancer eligible for cisplatin were randomized to:
- Arm A: neoadjuvant and adjuvant PADCEV + pembrolizumab
- Arm B: neoadjuvant gemcitabine + cisplatin (standard of care)
Curative-intent surgery (radical cystectomy) was performed after completion of pre-operative therapy. The primary endpoint is event-free survival (EFS), defined from randomization to disease progression preventing cystectomy (or failure to undergo cystectomy in the presence of residual disease), gross residual disease at surgery, local or distant recurrence (per blinded independent central review), or death from any cause. Key secondary endpoints include overall survival (OS) and pathologic complete response (pCR).
The companies reported that EV-304 met EFS and that OS—identified as a key secondary endpoint—was also significantly improved at interim analysis, along with pCR.
Why EV-304 Matters in Perioperative MIBC?
For patients with muscle-invasive disease, curative-intent management typically involves cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy in those who are eligible for cisplatin. Even with optimal local therapy, recurrence remains common, underscoring the need for more effective perioperative systemic approaches.
Investigators and sponsors framed EV-304 as an important step toward expanding a platinum-free perioperative strategy in earlier-stage bladder cancer. Christopher Hoimes, DO (Duke Cancer Institute), a principal investigator for EV-304, emphasized the high rate of progression to metastatic disease despite existing options and described EV-304 as a key milestone for the field. He also linked the EV-304 findings with prior evidence from EV-303, suggesting perioperative enfortumab vedotin plus pembrolizumab could meaningfully shift the treatment pathway across eligibility subgroups.
EV-304 and EV-303 trials
While EV-304 specifically enrolled cisplatin-eligible patients, the announcement highlighted the broader arc of evidence for the combination across MIBC populations when considered alongside the Phase 3 EV-303 (KEYNOTE-905) program in cisplatin-ineligible patients.
Astellas and Pfizer pointed to the recent U.S. FDA approval of PADCEV plus pembrolizumab (or pembrolizumab with berahyaluronidase alfa-pmph) as neoadjuvant therapy followed by adjuvant continuation after cystectomy for cisplatin-ineligible MIBC, based on EV-303. Against that backdrop, EV-304 extends the story into the cisplatin-eligible setting, with the companies positioning the combined EV-303 and EV-304 results as support for a potential new platinum-free standard in earlier-stage bladder cancer.
Moitreyee Chatterjee-Kishore, PhD, MBA (Astellas), said the EV-304 findings build on the recent U.S. approval in cisplatin-ineligible MIBC and reinforce the potential of PADCEV plus pembrolizumab to improve outcomes for a broader MIBC population. Jeff Legos, PhD, MBA (Pfizer), emphasized that the perioperative setting is now seeing significant survival benefit without the need for platinum-based chemotherapy and described the results as signaling a new standard-of-care possibility.
“For the first time, patients with muscle-invasive bladder cancer are seeing significant survival benefits from combination therapy in a perioperative setting without the need for platinum-based chemotherapy, signaling the potential for a new standard of care for this community. The EV-304 results, combined with the recent unprecedented results from the EV-303 trial, showcase the promising future of this regimen as a cornerstone of care for bladder cancer regardless of cisplatin eligibility.”
Jeff Legos, PhD, MBA, Chief Oncology Officer, Pfizer, said
Conclusion
Together, the EV-304 and EV-303 trial results position perioperative enfortumab vedotin plus pembrolizumab as a potentially transformative strategy in muscle-invasive bladder cancer, demonstrating clinically meaningful survival benefits across cisplatin-eligible and cisplatin-ineligible populations.
By delivering significant improvements in event-free and overall survival without reliance on platinum-based chemotherapy, this combination challenges long-standing perioperative treatment paradigms and signals a possible shift toward a unified, platinum-free standard of care in earlier-stage bladder cancer, pending full data presentation and regulatory review.
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