Platinum-Free PADCEV Plus Pembrolizumab Improves Survival in Muscle-Invasive Bladder Cancer

The Phase 3 EV-304 KEYNOTE-B15 trial showed that perioperative enfortumab vedotin (PADCEV) plus pembrolizumab (Keytruda) significantly improved event-free survival and overall survival versus neoadjuvant gemcitabine and cisplatin in cisplatin-eligible muscle-invasive bladder cancer. The platinum-free regimen also increased pathologic complete response rates, reinforcing its potential to redefine perioperative care across bladder cancer populations.

Astellas Pharma and Pfizer reported positive topline results from an interim analysis of the Phase 3 EV-304 trial, also known as KEYNOTE-B15. The study evaluated PADCEV plus Keytruda as neoadjuvant and adjuvant therapy, administered before and after surgery, compared with standard neoadjuvant gemcitabine and cisplatin in cisplatin-eligible patients with MIBC. The trial met its primary endpoint of event-free survival and also demonstrated a statistically significant improvement in overall survival, a key secondary endpoint.

Importantly, EV-304 also met a secondary endpoint of pathologic complete response, showing a clinically meaningful improvement with neoadjuvant PADCEV plus pembrolizumab versus standard chemotherapy. According to the companies, the safety profile of the combination was consistent with previously reported data for 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,” said Dr. Christopher Hoimes, DO, Director of the Bladder Cancer Program CCI at Duke Cancer Institute and a principal investigator of EV-304.

MIBC accounts for roughly 30 percent of all bladder cancer cases worldwide. While cisplatin-based neoadjuvant chemotherapy followed by cystectomy remains the standard of care for eligible patients, outcomes remain suboptimal. Even after surgery, approximately half of patients experience disease recurrence. The EV-304 results therefore address a major unmet need in an earlier, potentially curable disease setting.

From a development perspective, the data reinforce momentum generated by the related Phase 3 EV-303 trial, also known as KEYNOTE-905, which recently supported U.S. regulatory approval of PADCEV plus pembrolizumab in cisplatin-ineligible patients with MIBC.

“Building on the recent U.S. approval for cisplatin-ineligible patients living with MIBC, these positive EV-304 findings reinforce the potential of PADCEV plus pembrolizumab to improve survival outcomes for a broad population of patients living with muscle-invasive bladder cancer. Together with the EV-303 data, these results strengthen the evidence supporting this combination regimen as a treatment option for patients regardless of cisplatin eligibility,” said Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development at Astellas.

The EV-304 trial is an ongoing, open-label, randomized Phase 3 study comparing neoadjuvant and adjuvant PADCEV plus pembrolizumab with neoadjuvant gemcitabine and cisplatin. Patients underwent curative-intent cystectomy following preoperative systemic therapy. Event-free survival was defined broadly, capturing disease progression that precludes surgery, residual disease at surgery, recurrence, or death from any cause, with overall survival and pathologic complete response as key secondary endpoints.

“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,” said Jeff Legos, PhD, MBA, Chief Oncology Officer at Pfizer.

Mechanistically, enfortumab vedotin targets Nectin-4, a cell surface protein highly expressed in bladder cancer. Following binding and internalization, the conjugated cytotoxic payload monomethyl auristatin E disrupts microtubules, leading to cell cycle arrest and apoptosis. Pembrolizumab complements this activity through immune checkpoint inhibition, enhancing antitumor immune responses.

While PADCEV plus pembrolizumab is already approved in multiple regions for locally advanced or metastatic urothelial cancer, the regimen is not yet approved for neoadjuvant and adjuvant use in cisplatin-eligible MIBC. The companies indicated that full EV-304 data will be presented at an upcoming medical congress and discussed with global health authorities to support potential regulatory filings.