NCCN Guidelines: Navigating ctDNA MRD Testing in Evolving MIBC Paradigms

A recent update to the NCCN Guidelines for Bladder Cancer incorporated circulating tumor DNA (ctDNA) molecular residual disease (MRD) testing following radical cystectomy. However, applying these recommendations in real-world clinical practice requires careful nuance.¹

According to Mamta Parikh, MD, MS, these updated guidelines apply to a narrow patient population, specifically, those who are immune checkpoint inhibitor naive prior to surgery, mirroring the eligibility criteria of the phase 3 IMvigor011 trial (NCT04660344).² In contrast, modern muscle-invasive bladder cancer (MIBC) management increasingly favors aggressive upfront perioperative regimens. Protocols such as such as NIAGARA(durvalumab [Imfinzi]; NCT03732677), KEYNOTE-905 (NCT03924895) , and KEYNOTE-B15(NCT04700124) mandate continuing adjuvant therapy regardless of pathologic status or MRD findings.^3-5

She emphasized that while ctDNA holds significant prognostic potential, current evidence does not yet support altering established adjuvant treatment courses in the perioperative setting, where adherence to trial-proven regimens remains the standard of care.

Parikh is the medical director of Genitourinary Malignancies at the UC Davis Comprehensive Cancer Center and member of the NCCN Guidelines Panel for Bladder Cancer.

Transcript:

[This] is an important opportunity to clarify the current NCCN guidelines regarding MRD monitoring. This is a very specific guideline for patients who did not receive an immune checkpoint inhibitor prior to radical cystectomy, and it is based on the eligibility criteria of patients enrolled on the IMvigor011 study, so these guidelines are narrow in the context of the evolving landscape of [MIBC] management.

We are now taking a much more aggressive perioperative approach that incorporates checkpoint inhibitor therapy both before and after surgery, and in those regimens, by definition, perioperative management implies continuation of therapy postoperatively. In the case of NIAGARA, that involves continuing durvalumab, and in the case of the KEYNOTE-905 and KEYNOTE-B15 studies, that includes continuation of enfortumab vedotin [Padcev] and pembrolizumab [Keytruda]. We do not have enough data about whether ctDNA testing carries the same actionable weight in these settings, but we know these studies were designed as a perioperative approach, and in these trials, regardless of pathologic status at the time of radical cystectomy, patients continued on to receive adjuvant therapy, and all of these studies were positive studies that benefited patients. In the perioperative setting, we need to be mindful that continuation of adjuvant therapy is the current standard, and we do not have sufficient ctDNA data to inform whether we can change that at present.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Bladder Cancer, Version 2.2026. Accessed July 31, 2026. https://tinyurl.com/3j78syzt
2. Bellmunt J, Gupta S, Durán MÁ, et al. Patient-reported outcomes from IMvigor011: a phase 3 study of circulating tumor (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer (MIBC). J Clin Oncol. 2026;44(suppl 16):4627. doi:10.1200/JCO.2026.44.16_suppl.4627
3. Van Der Heijden MS, Galsky MD, Joshi R, et al. Urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) in patients (pts) with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. J Clin Oncol. 2026;44(suppl 7):636. doi:10.1200/JCO.2026.44.7_suppl.636
4. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
5. PADCEV plus Keytruda significantly improves survival for patients with muscle-invasive bladder cancer regardless of cisplatin eligibility. News release. Astellas Pharma. December 17, 2025. Accessed August 3, 2026. https://tinyurl.com/2u6cfrhs