Muscle-invasive bladder cancer (MIBC) represents approximately 30% of the ~614,000 annual global bladder cancer cases, ranking it as the ninth most common malignancy worldwide. While neoadjuvant cisplatin-based chemotherapy followed by cystectomy remains the standard for eligible patients, up to half of those with MIBC are ineligible for cisplatin due to comorbidities, renal impairment, or other factors, leaving them with limited perioperative options and high recurrence rates—nearly 50% even post-surgery. On November 21, 2025, the U.S. Food and Drug Administration (FDA) approved a transformative regimen: PADCEV® (enfortumab vedotin-ejfv), a Nectin-4-directed antibody-drug conjugate (ADC), in combination with Keytruda® (pembrolizumab) or Keytruda QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), for neoadjuvant treatment followed by adjuvant therapy post-cystectomy in cisplatin-ineligible adults with MIBC.
This accelerated approval—months ahead of schedule—is grounded in the pivotal Phase 3 EV-303/KEYNOTE-905 trial, an ongoing, open-label, randomized study involving three arms: neoadjuvant/adjuvant pembrolizumab alone, surgery alone, or the combination (Arm C). The primary endpoint, event-free survival (EFS), defined as time from randomization to disease progression precluding surgery, surgical ineligibility, incomplete resection, recurrence, or death—favored the combination arm over surgery alone, achieving a hazard ratio (HR) of 0.40 (95% CI: 0.28-0.57; p<0.0001). This translates to a 60% risk reduction, with 74.7% event-free probability at two years versus 39.4%, and median EFS not reached compared to 15.7 months. Secondary endpoints reinforced efficacy: overall survival (OS) showed a 50% risk reduction (HR=0.50; 95% CI: 0.33-0.74; p=0.0002), with 79.7% two-year survival versus 63.1% and median OS not reached versus 41.7 months. Pathological complete response rates also improved significantly.
Safety profiles align with prior data, though Grade ≥3 adverse events occurred in 71.3% of the combination arm versus 45.9% in surgery alone. Common reactions (≥20%) include hyperglycemia, anemia, rash, fatigue, and peripheral neuropathy. PADCEV carries a boxed warning for severe skin reactions like Stevens-Johnson syndrome/toxic epidermal necrolysis.
This first-in-class ADC/PD-1 inhibitor perioperative regimen positions itself as a potential new standard of care, addressing decades of unmet needs. As noted by trial investigator Dr. Matthew Galsky, it could be “practice-changing” for underserved patients. Ongoing trials, such as EV-304/KEYNOTE-B15 for cisplatin-eligible populations, may further expand its reach. Developed through collaboration among Pfizer, Astellas, and Merck, this approval heralds an era of precision oncology in urologic cancers, enhancing survival prospects and quality of life.
