EU Regulators Back Wider Use of Keytruda-Padcev Combination Before Bladder Cancer Surgery, Following Strong Survival Data

On September 18, 2026, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recommended extending EU approval of the checkpoint inhibitor pembrolizumab (Keytruda) combined with the antibody-drug conjugate enfortumab vedotin (Padcev) to all adults with resectable muscle-invasive bladder cancer (MIBC) who are candidates for surgery — not just the cisplatin-ineligible subset the EU had approved months earlier — based on a Phase 3 trial showing a 35% reduction in the risk of death when the combination is given before and after surgery.

A Second, Broader Green Light for a Regimen Already Reshaping Bladder Cancer Care

Muscle-invasive bladder cancer has long been treated with a blunt instrument: cisplatin-based chemotherapy before surgical removal of the bladder, a regimen that a substantial share of patients cannot tolerate because of kidney function, hearing loss risk, or other comorbidities. For those cisplatin-ineligible patients, options before surgery have historically been thin, and outcomes after cystectomy alone have been sobering.

That picture has been shifting quickly in 2026. In June, the European Commission approved pembrolizumab plus enfortumab vedotin for cisplatin-ineligible MIBC patients, based on the KEYNOTE-905/EV-303 trial, which found a 60% reduction in the risk of disease progression or death and a 50% reduction in mortality risk compared with surgery alone, along with a pathologic complete response rate of 57.1% versus just 8.6%. The U.S. FDA had already cleared the same narrower indication for this population in late 2025.

The news now is that CHMP has recommended taking the next step: opening the combination up to essentially anyone medically fit for bladder removal surgery, cisplatin-eligible or not. If the European Commission finalizes the recommendation as expected, EU practice will align with the FDA, which approved this same all-comers indication on July 10, 2026 — explicitly stating the new approval "extends the prior approval for the regimen in this setting from patients who are cisplatin-ineligible to all patients with MIBC who are candidates for cystectomy."

The Trial Behind the Expansion

The CHMP recommendation rests on KEYNOTE-B15/EV-304 (NCT04700124), a Phase 3, randomized, open-label, multicenter trial enrolling 808 patients with cisplatin-eligible resectable MIBC. Patients were randomized to receive pembrolizumab plus enfortumab vedotin before and after surgery, or the long-standing chemotherapy standard, neoadjuvant gemcitabine plus cisplatin, ahead of cystectomy.

The results, published in the New England Journal of Medicine, are genuinely striking for a disease where progress has often come in small increments. Event-free survival: the combination cut the risk of disease progression, recurrence, or death by 47% (hazard ratio 0.53; 95% CI, 0.41–0.70; P < .001). Median event-free survival was not yet reached in the treatment arm, versus 48.5 months with chemotherapy. At two years, 79.4% of patients on the combination remained event-free, compared with 66.2% on chemotherapy. Overall survival: the combination reduced the risk of death by 35% (hazard ratio 0.65; 95% CI, 0.48–0.89; two-sided P = .006). Two-year overall survival was 86.9% with the combination versus 81.3% with chemotherapy. Pathologic complete response: among patients who went on to surgery, 55.8% had no detectable residual cancer in the removed bladder tissue, versus 32.5% with chemotherapy — a marker strongly associated with long-term outcomes in bladder cancer.

Why This Combination Works

Pembrolizumab is a PD-1 checkpoint inhibitor, the class of immunotherapy that unleashes the body's own T cells against tumor cells by blocking a molecular "off switch" that cancers exploit to evade immune attack. Enfortumab vedotin is an antibody-drug conjugate: an antibody targeting Nectin-4, a protein highly expressed on urothelial cancer cells, chemically linked to a potent microtubule-disrupting payload that is delivered directly into the tumor cell rather than circulating systemically like conventional chemotherapy. The pairing — already approved for metastatic urothelial cancer since 2023 — is now being tested and, increasingly, approved in the earlier, potentially curative perioperative setting, where the goal is not just to shrink an established metastatic tumor but to eliminate micrometastatic disease before it can take hold after surgery.

The Caveats That Matter

This is real, clinically meaningful progress, but several qualifications belong alongside the good news. First, this is a CHMP recommendation, not a final approval — the European Commission, which almost always follows CHMP's scientific opinion, is expected to issue its formal marketing authorization decision in the fourth quarter of 2026. Until then, the broader indication is not yet approved in the EU (though it already is in the United States).

Second, the combination is not free of toxicity. Grade 3 or higher adverse events occurred in 75.7% of patients on the combination versus 67.2% on chemotherapy, and enfortumab vedotin in particular drove elevated rates of skin reactions (63.5%) and peripheral neuropathy (36%), the latter of which can be dose-limiting and, in some cases, only partially reversible. Immune-related toxicities associated with pembrolizumab — including pneumonitis, colitis, hepatitis, and endocrine disorders — require ongoing monitoring and, at times, corticosteroid management. Regulatory summaries of the trial also note a small number of treatment-related deaths in the combination arm.

Third, the trial compared the combination against chemotherapy alone, not against chemotherapy plus a checkpoint inhibitor or other emerging regimens, so exactly how this approach should be sequenced against other evolving bladder cancer strategies is still being worked out by clinicians.

What's Next

Assuming the European Commission finalizes the CHMP recommendation on schedule, eligible patients across the EU should gain access to the expanded indication by early 2027, mirroring what is already available in the United States. Longer follow-up from KEYNOTE-B15/EV-304 will also be watched closely to see whether the substantial early survival advantage persists, and whether bladder-preservation strategies can eventually be built around this level of pathologic response.

Bottom Line

Regulators on both sides of the Atlantic are now aligned, or nearly so, in recommending that pembrolizumab plus enfortumab vedotin be offered before and after bladder-removal surgery to essentially all medically eligible patients with muscle-invasive bladder cancer, not just those who cannot tolerate cisplatin — a shift grounded in a Phase 3 trial showing meaningfully better survival and dramatically higher rates of complete pathologic response than the decades-old chemotherapy standard, tempered by real increases in serious side effects and the fact that the EU's expanded approval is still pending final sign-off.