New data presented at the European Association of Urology (EAU) 2026 congress are offering hope for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The KEYNOTE-905/EV-303 trial demonstrates that a combination of pembrolizumab and enfortumab vedotin, administered both before and after surgery, significantly improves event-free survival, overall survival, and pathologic complete response rates in this patient population.
For decades, platinum-based chemotherapy has been the standard first-line treatment for MIBC. However, a substantial number of patients are unable to receive cisplatin due to pre-existing conditions or other factors. This leaves a critical need for alternative, effective therapies. The KEYNOTE-905/EV-303 trial addresses this gap, offering a potential new standard of care for these patients. This combination therapy represents a significant advancement in the treatment of muscle-invasive bladder cancer, particularly for those who previously had limited options.
KEYNOTE-905/EV-303 Trial Design and Results
The Phase 3 KEYNOTE-905/EV-303 trial, involving 344 patients with previously untreated MIBC, evaluated the efficacy of neoadjuvant pembrolizumab and enfortumab vedotin followed by surgery, and then adjuvant enfortumab vedotin in combination with pembrolizumab, followed by pembrolizumab alone, compared to surgery alone. Patients were candidates for radical cystectomy with pelvic lymph node dissection but were ineligible for or declined cisplatin-based chemotherapy. The study’s primary endpoint was event-free survival (EFS), with overall survival (OS) and pathologic complete response (pCR) rate as key secondary endpoints.
The results, approved by the FDA in November 2025, showed statistically significant improvements in all three endpoints. Median EFS was not reached in the pembrolizumab and enfortumab vedotin arm, compared to 15.7 months in the surgery-alone arm (Hazard Ratio 0.40; 95% Confidence Interval: 0.28-0.57; p-value <0.0001). Median OS was also significantly improved, not reached (NR) in the combination therapy arm versus 41.7 months in the surgery-alone arm (HR 0.50; 95% CI: 0.33-0.74; p-value 0.0002).
Understanding the Therapies
Pembrolizumab (Keytruda) is an anti-PD-1 antibody, a type of immunotherapy that helps the body’s immune system recognize and attack cancer cells. Enfortumab vedotin (Padcev) is an antibody-drug conjugate that targets nectin-4, a protein found on bladder cancer cells, delivering a cytotoxic agent directly to the tumor. The combination leverages two distinct mechanisms to combat the cancer, potentially leading to a more robust and durable response. The recommended dose of pembrolizumab for neoadjuvant treatment is 200 mg administered intravenously every three weeks in combination with enfortumab vedotin-ejfv, according to the FDA.
Impact on Patient Care
Dr. Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent and principal investigator of the KEYNOTE-905 trial, highlighted the significance of these findings for patients ineligible for cisplatin-based chemotherapy, who historically have faced high rates of disease recurrence and a poor prognosis even after bladder removal. The combination therapy offers a new avenue for improving outcomes in this challenging patient population.
Merck, known as MSD outside the United States and Canada, announced the positive topline results in August 2025, noting that This represents the first systemic therapy to improve survival when used before and after surgery for patients with MIBC who are ineligible for cisplatin-based chemotherapy.
Looking ahead, further research will focus on identifying biomarkers that can predict which patients are most likely to benefit from this combination therapy, and on exploring its potential in other bladder cancer subtypes. The integration of pembrolizumab and enfortumab vedotin into clinical practice promises to reshape the treatment landscape for muscle-invasive bladder cancer, offering renewed hope for patients facing this difficult diagnosis.
This information is for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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