A paradigm shift in MIBC: New systemic therapies lead the way

In this video, Jason M. Hafron, MD, CMO, highlights the rapid and transformative progress occurring in the treatment of muscle-invasive bladder cancer (MIBC). He describes the current moment as a major paradigm shift driven largely by new systemic therapies that are reshaping standards of care.

Hafron begins by noting the impact of the NIAGARA trial, which evaluated durvalumab (Imfinzi) combined with gemcitabine/cisplatin (gem/cis) followed by adjuvant durvalumab after cystectomy. The positive results have effectively established what he calls the “NIAGARA protocol” as the emerging standard of care: neoadjuvant gem/cis plus durvalumab, cystectomy, and adjuvant durvalumab. He considers this regimen something that should be offered to all eligible patients with MIBC today.

He then focuses on the growing significance of antibody–drug conjugates, especially enfortumab vedotin-ejfv (EV, Padcev), when paired with pembrolizumab (Keytruda). Building on the EV-301 trial—which showed a dramatic survival improvement in the metastatic setting—recent results from KEYNOTE-905/EV-303 presented at ESMO demonstrate that EV plus pembrolizumab given before cystectomy yields major benefits for cisplatin-ineligible patients. The regimen met all key end points and is poised, pending regulatory approval, to become the new first-line neoadjuvant standard, pushing traditional chemotherapy further down the treatment algorithm.

One particularly striking finding from KEYNOTE-905/EV-303 is the nearly 60% pathologic complete response rate. Hafron suggests that such deep responses raise the possibility of future cystectomy-sparing strategies. Although more research is needed, especially through larger trials, he points to earlier phase 2 work—such as the Hoosier trial led by Matthew Galsky, MD—that supports exploring systemic-only approaches.

Although he acknowledges that cystectomy will remain essential for certain patients, Hafron underscores the potential clinical and quality-of-life benefits of more precisely determining who truly requires surgery. Ultimately, he sees these advances as setting the stage for a more personalized, less morbid management paradigm in muscle-invasive bladder cancer.