The National Comprehensive Cancer Network (NCCN) has updated its guidelines for bladder cancer to reflect changes to WHO’s Classification of Tumours: Urinary and Male Genital Tumours and to account for new treatment options and updates to systemic therapies for advanced and metastatic disease.

“Within the category of metastatic disease, several new agents and combination regimens have been studied and seem to be superior to those that were previously considered standard therapies,” the authors wrote. “In particular, immune checkpoint inhibitors (ICIs), antibody–drug conjugates, and targeted therapies have emerged as new options for the treatment of metastatic bladder cancer.”

The NCCN’s updates include:

• A change from “variant” to “subtype” when describing morphologic categories within a tumor type in response to WHO’s 2022 revisions.
• A revised list of invasive urothelial carcinoma and noninvasive urothelial neoplasm subtypes, also to align with the 2022 WHO Classification.
• An update to the Principles of Pathology Management to better detail what should be included in a pathology report for biopsy, transurethral resection of the bladder tumor (TURBT), or cystectomy specimens.
• The NCCN now considers pembrolizumab an option for select patients with bacillus Calmette-Guerin (BCG) -unresponsive or -intolerant, high-risk non–muscle-invasive bladder cancer (NMIBC), specifically for patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) (with or without papillary) tumors as a category 2A recommendation.
• In the May 2024 NCCN Guidelines Insight published in the Journal of the National Cancer Network , the authors wrote that pembrolizumab may be considered for patients without CIS as a category 2B recommendation, which, while it does not fall within the FDA-approved indication, is supported by clinical trial evidence.
• The NCCN panel offered similar guidance for nadofaragene firadenovec, saying it chose to mirror the pembrolizumab recommendations because the two would be considered under similar circumstances.
• The combination of pembrolizumab and enfortumab vedotin was added as a preferred regimen for patients, both eligible and ineligible for cisplatin. The authors noted that the panel “was particularly enthusiastic about the noteworthy results from the phase III EV-302 trial, with some panel members stating that these results entirely change the way that clinicians should be thinking about first-line decision-making.”
• The panel voted to list enfortumab vedotin 1 pembrolizumab as the only preferred first-line regimen in both the cisplatin-eligible and cisplatin-ineligible patients.
• The panel added nivolumab, gemcitabine, and cisplatin followed by nivolumab maintenance therapy as a category 1 first-line therapy option for those eligible to receive cisplatin for locally advanced or metastatic disease.
• Although a January 2024 decision by the U.S. Food and Drug Administration limited erdafitinib eligibility to only those who had previously received, or were unable to receive, an ICI, NCCN opted to retain the erdafitinib recommendation for second-line therapy, postplatinum therapy, or other chemotherapy while it monitors future data.

The authors noted that molecular staging remains under development with the goal of allowing more refined approaches to determine prognosis and guide management so patient outcomes are optimized to improve the likelihood of a cure and organ preservation. “Experts surmise that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes across all disease stages,” the authors wrote.