PADCEV–KEYTRUDA Combination Delivers Survival Gains in High-Risk Bladder Cancer

The Phase 3 EV-303 (KEYNOTE-905) trial shows PADCEV™ (enfortumab vedotin) plus KEYTRUDA™ (pembrolizumab) is the first and only regimen to significantly extend event-free and overall survival when used before and after surgery in cisplatin-ineligible muscle-invasive bladder cancer. The combination also achieved higher pathologic complete response rates, marking a potential new standard for a high-risk, previously underserved patient population.

A Breakthrough in a High-Risk Population

Patients with  muscle-invasive bladder cancer (MIBC) who cannot receive cisplatin-based chemotherapy have long faced limited options beyond surgery, with high recurrence rates and poor long-term outcomes. EV-303 addressed this gap by evaluating PADCEV plus KEYTRUDA in the neoadjuvant and adjuvant setting versus surgery alone, the current standard of care.

At the first interim analysis, the combination delivered a clinically meaningful and statistically significant improvement in event-free survival (EFS) — the trial’s primary endpoint — and in overall survival (OS), a key secondary endpoint. The pathologic complete response (pCR) rate was also significantly higher compared to surgery alone.

“Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy have not seen any treatment advance beyond surgery and face high rates of disease recurrence and a poor prognosis, even after having their bladder removed,” said Dr Christof Vulsteke, M.D., Ph.D., EV-303 principal investigator. “These EV-303 study results mark the first time a systemic treatment approach, used before and after surgery, significantly extended survival over standard-of-care surgery in this population, demonstrating the potential of this combination to address a critical unmet need.”

Trial Design and Safety

EV-303 is an ongoing, open-label, randomized Phase 3 study involving cisplatin-ineligible or cisplatin-declining patients with MIBC. Participants were assigned to surgery alone, neoadjuvant and adjuvant KEYTRUDA, or neoadjuvant and adjuvant PADCEV plus KEYTRUDA. The safety profiles for both the combination and KEYTRUDA monotherapy were consistent with their established tolerability.

Clinical and Regulatory Implications

PADCEV, a first-in-class Nectin-4–directed antibody-drug conjugate, works by delivering the cytotoxic payload MMAE directly into tumor cells, causing cell cycle arrest and apoptosis. Combined with KEYTRUDA’s PD-1 checkpoint inhibition, the regimen has already transformed treatment in advanced urothelial cancer.

“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,” said Moitreyee Chatterjee-Kishore, Ph.D., M.B.A., Head of Oncology Development at Astellas.

Next Steps

Results from EV-303 will be presented at a forthcoming congress and reviewed by regulatory agencies for potential approval in this indication. The combination is also being studied in cisplatin-eligible patients in the Phase 3 EV-304 (KEYNOTE-B15) trial. If approved, PADCEV plus KEYTRUDA could become the first perioperative systemic therapy to improve survival in cisplatin-ineligible MIBC.

Johanna Bendell, M.D., Oncology Chief Development Officer, Pfizer added: “PADCEV plus KEYTRUDA has already changed the treatment paradigm for patients with locally advanced or metastatic urothelial cancer as standard of care. 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.”