FDA Approves Padcev Plus Keytruda as First Platinum-Free Regimen for Muscle-Invasive Bladder Cancer

Pfizer and Astellas announced that the FDA has approved enfortumab vedotin-ejfv (Padcev), a Nectin-4-directed antibody-drug conjugate (ADC), in combination with pembrolizumab (Keytruda) or Keytruda QLEX, as neoadjuvant and adjuvant treatment for adult patients with muscle-invasive bladder cancer (MIBC), regardless of cisplatin eligibility.¹ The approval makes this the first platinum-free treatment regimen cleared for MIBC patients across both cisplatin-eligible and cisplatin-ineligible populations, expanding on a November 2025 approval that had covered only cisplatin-ineligible patients based on separate EV-303 trial data.¹

What clinical data supported the approval?

The expanded approval was based on the pivotal phase III EV-304 trial (also known as KEYNOTE-B15), which randomized cisplatin-eligible MIBC patients to receive either neoadjuvant and adjuvant Padcev plus Keytruda around curative-intent surgery, or standard neoadjuvant chemotherapy with gemcitabine and cisplatin.² The combination reduced the risk of tumor recurrence, progression, or death by 47% compared with chemotherapy, with 79.4% of patients event-free at two years versus 66.2% on standard of care.² The regimen also cut the risk of death by 35% and nearly doubled the pathological complete response rate at the time of surgery, 55.8% versus 32.5% with chemotherapy.² Grade 3 or higher adverse events occurred in 75.7% of patients on the Padcev-pembrolizumab regimen compared with 67.2% on chemotherapy, a safety profile the companies described as consistent with prior experience with the combination.²

In a company press release, Christopher Hoimes, DO, director of the Bladder Cancer Program and Center for Cancer Immunotherapy at Duke Cancer Institute and an EV-304 principal investigator, said delivering the regimen across both the neoadjuvant and adjuvant phases without platinum-based chemotherapy could offer a potential new standard of care, since the neoadjuvant phase helps shrink tumors and target undetectable cancer cells before surgery, while the adjuvant phase works to eliminate any residual disease afterward.¹

How does the Padcev-Keytruda mechanism work?

Padcev is a first-in-class ADC directed against Nectin-4, a protein highly expressed on bladder cancer cells. It binds to Nectin-4-expressing cells before being internalized, releasing the cytotoxic agent monomethyl auristatin E (MMAE) inside the cell to trigger cell cycle arrest and programmed cell death. Keytruda, a PD-1 inhibitor, works through a distinct immune-checkpoint mechanism, helping restore T-cell activity against tumor cells. Combining the two gives the regimen dual mechanisms of action, targeted cytotoxicity through the ADC and immune-mediated tumor clearance through checkpoint inhibition, an approach BioPharm International has previously noted has already reshaped the treatment paradigm for advanced urothelial cancer more broadly, following the earlier EV-302 trial that established the combination as first-line standard of care for metastatic disease.

How Does This Fit the Broader MIBC Treatment Picture?

MIBC accounts for roughly 30% of all bladder cancer cases, and even after cystectomy, approximately half of MIBC patients experience disease recurrence. Standard treatment has long centered on cisplatin-based chemotherapy before surgery, but a meaningful share of patients are ineligible for cisplatin due to kidney function or other health factors, leaving them without a comparably effective standard option. This approval addresses that gap directly by extending the regimen to both cisplatin-eligible and cisplatin-ineligible populations under a single indication, following a Priority Review designation the FDA granted for this application earlier in 2026.

What Happens Next?

Aamir Malik, executive vice president and chief U.S. commercial officer at Pfizer, said in a company accouncement that Padcev plus Keytruda has already established itself as the standard of care in first-line advanced bladder cancer, and the company is positioning this approval as extending that role into an earlier, potentially curative-intent setting. With the regimen now authorized across the full MIBC population regardless of cisplatin eligibility, the companies' focus shifts to broadening clinical adoption ahead of any competing platinum-free regimens that may enter later-stage development in the same setting.¹

References

1. U.S. FDA Approves PADCEV plus Keytruda as Neoadjuvant and Adjuvant Treatment for Muscle-Invasive Bladder Cancer Regardless of Cisplatin Eligibility. (2026 Jul 10). Pfizer. https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-padcevr-plus-keytrudar-neoadjuvant-and
2. Galsky MD, et al. (2026 Mar 2). Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. J Clin Oncol. https://ascopubs.org/doi/10.1200/JCO.2026.44.7_suppl.LBA630