Navigating NMIBC treatment complexity

By Laura Boyd

Up to 50% of patients with high-risk non–muscle-invasive bladder cancer (NMIBC) become unresponsive to BCG therapy due to refractory disease, relapse, or inadequate response

In patients who are BCG-naive or unresponsive, NMIBC treatment pathways are increasingly complex, particularly amid ongoing global BCG shortages. While radical cystectomy remains a definitive option, it is often unsuitable or undesirable due to its impact on quality of life. In this context, bladder-sparing alternatives – including intravesical chemotherapy, immune checkpoint inhibitors, and emerging gene therapies – are reshaping the treatment landscape. However, inconsistent efficacy, limited access, and a lack of standardized protocols continue to challenge clinical decision-making.

How are global BCG shortages influencing treatment pathways in NMIBC?

Ongoing shortages of BCG are disrupting standard treatment pathways and forcing clinicians to reconsider sequencing and selection strategies. In high-risk NMIBC, limited access to guideline-recommended therapy has led to increased use of off-label intravesical chemotherapy and emerging immunotherapy options. These constraints are particularly challenging in community settings, where newer agents may not be available and treatment decisions must balance efficacy, safety, and accessibility.

Which bladder-sparing therapies are showing promise for BCG-unresponsive patients?

For patients with BCG-unresponsive NMIBC, bladder-sparing options remain limited. Two approaches supported by clinical data include:

• Pembrolizumab, a checkpoint inhibitor associated with immune-related adverse events and variable durability of response
• Nadofaragene firadenovec, a non-replicating adenoviral vector–based gene therapy with 5-year follow-up data showing bladder preservation in nearly 50% of patients; regulatory approval is pending in Europe, Japan, and Canada

What are the emerging treatment options for BCG-naive high-risk NMIBC?

Several bladder-sparing therapies are under investigation for patients with BCG-naive high-risk NMIBC. Key approaches include:

• Gemcitabine–docetaxel, with 12-month recurrence-free survival of 92% in phase 2 prospective data
• PD-1/PD-L1 inhibitors combined with BCG, including sasanlimab, durvalumab, pembrolizumab, under evaluation in phase 3 trials such as CREST, POTOMAC, and KEYNOTE-676

What role do molecular diagnostics and biomarkers play in NMIBC surveillance and treatment planning?

Molecular diagnostics and biomarkers are increasingly used to support risk stratification, recurrence monitoring, and assessment of treatment response. Tools under investigation include:

• Urine tumor
• DNA profiling
• Methylation-based assays
• CpG-targeted sequencing

Novel targeted therapies are being evaluated in relation to biomarkers such as PD-L1 expression, FGFR3 mutations, and molecular subtypes.

These approaches offer high sensitivity and specificity, but integration into routine practice remains variable. Updates from ASCO GU 2025, EAU25, AUA 2025, and ASCO 2025 underscore the growing importance of diagnostic innovation in clinical decision-making.

Key takeaways

• Global BCG shortages are disrupting standard treatment pathways and complicating treatment sequencing in NMIBC
• Bladder-sparing options for BCG-unresponsive patients include checkpoint inhibitors and gene therapy, though access and durability remain variable
• For BCG-naive high-risk NMIBC, gemcitabine–docetaxel and PD-1/PD-L1 inhibitor combinations are under investigation in phase 3 trials
• Molecular diagnostics and biomarkers are gaining traction in NMIBC surveillance, but adoption in routine practice remains limited

Developed by EPG Health for Medthority, independently of any sponsor.