NCCN recommends ctDNA-MRD testing to guide adjuvant treatment post-cystectomy

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for Bladder Cancer to incorporate tumor-informed circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) testing into post-cystectomy management of muscle-invasive bladder cancer (MIBC).¹

The guideline revision represents the first instance in which ctDNA-MRD has been recognized as a prognostic and predictive biomarker in bladder cancer. According to the updated recommendations, clinicians may consider an FDA-approved personalized tumor-informed multiplex PCR–next-generation sequencing assay to stratify risk and guide the use of adjuvant immunotherapy in patients who have not previously received an immune checkpoint inhibitor.

The recommendation comes on the heels of the FDA approval of atezolizumab (Tecentriq) and the Signatera CDx assay for ctDNA-positive patients after cystectomy.² Signatera is a personalized, tumor-informed assay that identifies patient-specific mutations from tumor tissue and can be used to track those variants over time.

The updated NCCN recommendations provide a Category 1 designation—the highest level of evidence and consensus within NCCN—for Signatera-guided adjuvant atezolizumab initiated when ctDNA positivity is detected within 1 year following cystectomy. The recommendation reflects data from the phase 3 IMvigor011 study, which evaluated a ctDNA-guided treatment approach.³

“This guideline update marks an important turning point for patients with muscle-invasive bladder cancer,” said Matthew D. Galsky, MD, deputy director of the Mount Sinai Tisch Cancer Center, director of Genitourinary Medical Oncology, and co-director of the Center of Excellence for Bladder Cancer at the Mount Sinai Tisch Cancer Center, in a news release.¹ “For the first time, NCCN has incorporated ctDNA-MRD testing into clinical decision-making following cystectomy. These recommendations are supported by prospective phase 3 evidence showing that a ctDNA-guided approach, using Signatera, can help guide post-surgical treatment decisions.”

Data from IMvigor011

IMvigor011 (NCT04660344) was a randomized, double-blind, placebo-controlled phase 3 study that enrolled patients with MIBC who underwent cystectomy and were monitored with serial ctDNA testing for up to 12 months. Among 761 patients in the surveillance cohort, 250 who tested ctDNA positive entered the treatment phase and were randomly assigned to atezolizumab (n = 167) or placebo (n = 83).

In patients who were ctDNA-positive, the median disease-free survival was 9.9 months with atezolizumab compared with 4.8 months with placebo (HR, 0.64; 95% CI, 0.47 to 0.87; P = .0047). Median overall survival was 32.8 months vs 21.1 months, respectively (HR, 0.59; 95% CI, 0.39 to 0.90; P = .0131).

Additional results from the study also showed favorable outcomes among patients who tested serially negative on ctDNA testing.⁴ Among these patients, the DFS was 95% at 12 months and 88% at 24 months. According to the authors, these results indicate that patients who remain ctDNA-negative on serial testing may safely avoid adjuvant treatment.

These results supported the May 2026 FDA approval of atezolizumab and the Signatera CDx assay as a companion diagnostic for ctDNA-positive MIBC after cystectomy.

REFERENCES

1. NCCN recommends ctDNA-MRD testing using Signatera™ technology in landmark bladder cancer guideline update. News release. Natera, Inc. June 23, 2026. Accessed June 24, 2026. https://www.businesswire.com/news/home/20260623843077/en/NCCN-Recommends-ctDNA-MRD-Testing-Using-Signatera-Technology-in-Landmark-Bladder-Cancer-Guideline-Update

2. FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer in patients with molecular residual disease. News release. US Food & Drug Administration. May 15, 2026. Accessed June 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-muscle-invasive-bladder-cancer-patients-molecular

3. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. 2025;393(24):2395-2408. doi:10.1056/NEJMoa2511885

4. Natera announces positive surveillance analysis from the randomized phase III IMvigor011 trial in muscle-invasive bladder cancer. News release. Natera, Inc. April 5, 2024. Accessed June 24, 2026. https://www.natera.com/company/news/natera-announces-positive-surveillance-analysis-from-the-randomized-phase-iii-imvigor011-trial-in-muscle-invasive-bladder-cancer/