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

The FDA approved Keytruda plus Padcev as the first platinum-free regimen for muscle-invasive bladder cancer on July 10, 2026, expanding the combination to all patients regardless of cisplatin eligibility. The approval came five weeks ahead of the FDA’s PDUFA date.

Keytruda (pembrolizumab, Merck, MRK) or Keytruda QLEX given with Padcev (enfortumab vedotin-ejfv, Astellas/Pfizer, PFE) can now be used before and after bladder removal surgery for adults with muscle-invasive bladder cancer (MIBC). This extends the prior approval, which covered only patients ineligible for cisplatin chemotherapy, to the full MIBC population. MRK closed at $130.48 and PFE at $25.01 on July 23.

The trial

The approval rests on the Phase 3 KEYNOTE-B15 trial (EV-304, NCT04700124), which randomized 808 patients to perioperative Keytruda plus Padcev or to neoadjuvant gemcitabine plus cisplatin followed by surgery. The results:

• Event-free survival: 47% risk reduction (HR 0.53, 95% CI 0.41-0.70, p<0.0001). Median EFS was not reached in the Keytruda/Padcev arm versus 48.5 months for chemotherapy.
• Overall survival: 35% risk reduction (HR 0.65, 95% CI 0.48-0.89, p=0.0029). Median OS was not reached in either arm.
• Pathologic complete response: 55.8% of patients had no evidence of invasive cancer in the removed tissue, versus 32.5% for chemotherapy (p<0.0001).

The FDA’s approval notice confirmed the review was granted priority review and conducted under Project Orbis, with concurrent reviews in Australia, Canada, Switzerland, the UK, and Israel.

Why platinum-free matters

Cisplatin has been the standard neoadjuvant treatment for MIBC for over 20 years, but it is toxic. Kidney damage, hearing loss, and nerve damage are common side effects, and up to half of patients cannot tolerate it. The Keytruda plus Padcev combination replaces cisplatin with a PD-1 inhibitor and an antibody-drug conjugate (ADC), attacking the tumor through immune activation and direct cell killing without the platinum toxicity.

The prior approval, based on the KEYNOTE-905 trial in cisplatin-ineligible patients, showed a 60% reduction in EFS events and a 50% reduction in mortality versus surgery alone. The KEYNOTE-B15 data now extends the benefit to cisplatin-eligible patients, where the combination beat chemotherapy head-to-head rather than comparing to surgery alone.

What to watch

The pathologic complete response rate of 55.8% is an early signal, not a guarantee of long-term cure. Longer follow-up from KEYNOTE-B15 will show whether the EFS and OS benefits hold at five and ten years. The combination carries real risks: serious adverse reactions occurred in 27% of patients in the neoadjuvant phase, and fatal adverse reactions occurred in 1.7%. Peripheral neuropathy, skin reactions, and pneumonitis are among the labeled warnings. For Merck, every new Keytruda indication extends the franchise before its 2028 patent cliff. For Pfizer and Astellas, Padcev gains a larger addressable population in the curative-intent setting.

What It Means for the Trade

Neither stock needs this: MRK at $130.48 is a Keytruda-earnings story and PFE at $25.01 is a yield-plus-berobenatide story. But the approval changes the MIBC math for both franchises more than the market reaction suggested. KEYNOTE-B15 is the first regimen to beat cisplatin head-to-head in the neoadjuvant setting in over 20 years, and it does so with a 55.8% pathologic complete response rate versus 32.5% — a gap that pathologists and surgeons will see in every cystectomy specimen. For the Padcev franchise, moving into cisplatin-eligible patients roughly doubles the perioperative addressable population beyond the KEYNOTE-905 ineligibles.

For Merck, the strategic value is sequencing: every indication locked in before 2028 extends the tail value of the franchise and strengthens the argument that Keytruda’s biosimilar erosion will be gradual rather than cliff-like. This approval is not a reason to buy MRK, but it is a reason the 2028 cliff keeps looking more like a slope.

Clinical Context

The hazard ratios are what matter: EFS HR 0.53 (95% CI 0.41-0.70) and OS HR 0.65 (0.48-0.89), both with the lower bound of the confidence interval well clear of 1.0. Median EFS not reached in the Keytruda/Padcev arm versus 48.5 months on chemotherapy is a durable separation, and the pCR doubling is the mechanistic evidence that the tumor is actually being eradicated, not merely controlled. But keep two caveats in view. First, 55.8% pCR is an early surrogate — the five- and ten-year follow-up decides whether this is cure improvement or timing shift. Second, the safety price is real: 27% serious adverse reactions in the neoadjuvant phase and 1.7% fatal adverse reactions, against a regimen that is supposed to spare patients platinum toxicity. Replacing cisplatin does not mean replacing toxicity; it means trading nephrotoxicity and ototoxicity for neuropathy, skin reactions, and pneumonitis.

The platinum-free label also opens the combination to the up-to-half of MIBC patients who cannot tolerate cisplatin at all — that population previously had only KEYNOTE-905’s comparison to surgery alone.

Risks and What Could Go Wrong

1. Long-term durability disappoints. Immune-based pCR advantages have historically held better than chemo-based ones, but 10-year bladder cancer data has surprised before.
2. Toxicity limits real-world adoption. A 1.7% fatal adverse reaction rate in a curative-intent population will make community urologists conservative about patient selection.
3. Reimbursement pressure on combination pricing in the perioperative setting, where both components are expensive and the payer argument is about a finite treatment window rather than chronic therapy.