New Drug Combination Improves Outcomes for Muscle-Invasive Bladder Cancer

A new combination therapy of pembrolizumab and enfortumab vedotin has demonstrated significant improvements in event-free survival and overall survival for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-based chemotherapy. This treatment approach has received FDA approval for both neoadjuvant treatment before cystectomy and adjuvant treatment following surgery.

What is Muscle-Invasive Bladder Cancer?

Muscle-invasive bladder cancer is an aggressive form of the disease where cancer cells have grown into the muscle of the bladder wall, increasing the risk of spread. Patients who are ineligible for cisplatin-based chemotherapy—a common first-line treatment—have historically had limited options.

The KEYNOTE-905/EV-303 Trial: A Breakthrough in Treatment

The efficacy of pembrolizumab and enfortumab vedotin was evaluated in the KEYNOTE-905/EV-303 clinical trial (NCT03924895). This open-label, randomized, multicenter trial involved 344 patients with previously untreated muscle-invasive bladder cancer who were candidates for radical cystectomy with pelvic lymph node dissection but were ineligible for or declined cisplatin-based chemotherapy.

Patients were randomized to receive either:

• Neoadjuvant pembrolizumab and enfortumab vedotin followed by surgery, then adjuvant enfortumab vedotin in combination with pembrolizumab, followed by pembrolizumab alone.
• Immediate surgery alone.

Significant Improvements in Survival

The trial showed statistically significant improvements in both event-free survival (EFS) and overall survival (OS) for patients treated with the pembrolizumab and enfortumab vedotin combination before and after radical cystectomy and pelvic lymph node dissection compared to those who underwent surgery alone.

Specifically:

• Median event-free survival was not reached (NR) in the pembrolizumab and enfortumab vedotin arm (95% CI: 37.3, NR) compared to 15.7 months (95% CI: 10.3, 20.5) in the surgery-alone arm (Hazard Ratio [HR] 0.40; 95% CI: 0.28, 0.57; p-value <0.0001).
• Median overall survival was NR in the pembrolizumab and enfortumab vedotin arm (95% CI: NR, NR) compared to 41.7 months (95% CI: 31.8, NR) in the surgery-alone arm (HR 0.50; 95% CI: 0.33, 0.74; p-value 0.0002).

FDA Approval and Safety Profile

On November 21, 2025, the Food and Drug Administration (FDA) approved pembrolizumab (Keytruda, Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) in combination with enfortumab vedotin-ejfv (Padcev, Astellas Pharma) for this indication. The overall safety profile observed in the KEYNOTE-905/EV-303 trial was consistent with that seen in previous trials of these drugs in advanced urothelial cancer FDA.

What This Means for Patients

This new combination therapy offers a promising treatment option for patients with muscle-invasive bladder cancer who cannot receive cisplatin-based chemotherapy. The significant improvements in event-free and overall survival represent a major step forward in the management of this aggressive disease. Research indicates this approach is becoming a new standard of care.