“Game-Changing” Keytruda-Padcev Combo Gets FDA Nod for Muscle-Invasive Bladder Cancer

The FDA has granted approval to the combination of Merck’s Keytruda (pembrolizumab) with Pfizer and Astellas’ Padcev (enfortumab vedotin-ejfv) as neoadjuvant and adjuvant therapy in adult patients with muscle-invasive bladder cancer (MIBC) who are unable to receive cisplatin-based chemotherapy.

This potentially game-changing combo marks the first time a systemic immunotherapy + antibody-drug conjugate (ADC) regimen has been approved for perioperative treatment of MIBC.

The approval also includes Keytruda’s new subcutaneous formulation, Keytruda Qlex.

Related: FDA Approves Zusduri as First Non-Surgical, Chemoablative Option for Recurrent Bladder Cancer Subset

MIBC is an aggressive disease requiring radical intervention that typically includes neoadjuvant cisplatin chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC + PLND).

However, a substantial fraction of patients are cisplatin-ineligible, often because of impaired kidney function, advanced age or comorbidities, forcing them to proceed directly to surgery.

For these patients, outcomes have historically been poor: even after bladder removal, many face a high risk of recurrence.

The new regimen provides perioperative systemic therapy (both before and after surgery), offering a chance to lower recurrence risk and improve long-term survival.

“We are honored to provide these patients who previously had only one option — surgery — with a choice to receive their immunotherapy either intravenously or subcutaneously,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in a news release from the company.

The approval of the Keytruda + Padcev combo is supported by data from the Phase III KEYNOTE-905 (also called EV-303) trial, which was conducted in collaboration with Pfizer and Astellas.

After a median follow-up of 25.6 months, administration of Keytruda plus Padcev perioperatively demonstrated a 60% reduction in the risk of event-free survival (EFS) events versus surgery alone in patients with MIBC who are not eligible for or declined cisplatin-based chemotherapy.

The Keytruda and Padcev combo also demonstrated a 50% improvement in overall survival (OS) versus surgery alone.

The trial demonstrated a statistically significant difference in pathologic complete response (pCR) rate (57.1% vs. 8.6%).

The data were presented at the European Society for Medical Oncology (ESMO) Congress held in Berlin, Germany, in October.

The combination is the first systemic therapy in decades proven to extend survival when used before and after cystectomy in cisplatin-ineligible MIBC, offering what Pfizer, Astellas and Merck developers have been touting as “game changing” and a new “standard of care.”

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Jeff Legos, PhD, MBA, chief oncology officer, Pfizer, said in a statement from the company: “Today’s approval, granted months earlier than anticipated, ushers in a new era of treatment for cisplatin-ineligible patients with MIBC who have long been underserved by existing treatments. Padcev plus pembrolizumab is the first and only FDA-approved perioperative treatment regimen to demonstrate a meaningful survival advantage compared to surgery alone, positioning it to reshape the treatment landscape and bring new hope to patients and families.”

Matthew Galsky, MD, director of Genitourinary Medical Oncology at the Mount Sinai Tisch Cancer Center, and EV-303 trial investigator, said: “Enfortumab vedotin plus pembrolizumab is poised to address a critical unmet need. Half of patients with MIBC may experience cancer recurrence even after having their bladder removed, and many of these patients are ineligible to receive cisplatin. This approval, based on striking event-free and overall survival benefits, may represent an important practice-changing advance for these patients who’ve had no new options in decades.”