At the recent ASCO Annual Meeting, Professor Michiel S. van der Heijden from the Netherlands Cancer Institute (NKI) presented the latest biomarker analysis from the Phase III NIAGARA trial. The study investigated the dynamics of urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) receiving perioperative durvalumab in combination with chemotherapy, evaluating their utility in predicting pathological complete response (pCR) and event-free survival (EFS).01. Background: Addressing the Limitations of ctDNA in Assessing Local Residual Disease
The NIAGARA trial previously established that adding durvalumab to neoadjuvant chemotherapy (gemcitabine plus cisplatin [GemCis]) significantly improves EFS and overall survival (OS). However, prior ctDNA data indicated that while ctDNA positivity is highly predictive of non-pCR, a significant portion of ctDNA-negative patients still fail to achieve pCR. To address this gap, this sub-analysis introduced utDNA testing to provide a “dual-compartment” (urine and plasma) liquid biopsy assessment, aiming to enhance the accuracy of identifying local response and inform individualized bladder-sparing strategies.
02. utDNA Clearance: Superior Performance in the Durvalumab Combination Arm
The study utilized a personalized, tumor-informed assay (Signatera). Baseline data showed that the vast majority of MIBC patients were utDNA-positive. Following neoadjuvant treatment and prior to radical cystectomy (RC), the utDNA clearance rate was significantly higher in the durvalumab plus chemotherapy arm compared to the chemotherapy-alone arm. Data confirmed that regardless of the treatment regimen, pre-RC utDNA clearance was associated with superior EFS, whereas persistent utDNA positivity heralded a poor prognosis.
03. Predicting pCR: The Edge of utDNA in Reflecting Local Response
utDNA demonstrated superior potential over ctDNA in predicting pCR. According to the results, patients who achieved utDNA negativity prior to surgery had a 72% probability of reaching pCR. While not a perfect predictor, utDNA proved more sensitive than ctDNA in reflecting the status of the local tumor bed. utDNA positivity was highly correlated with local residual disease, including both non-muscle-invasive and muscle-invasive residual tumors.
04. Combined Analysis: Distinctive Roles for ctDNA and utDNA
A combined analysis of plasma ctDNA and urinary utDNA revealed differential associations with pathological staging at the time of cystectomy:
- Plasma ctDNA: Primarily reflects systemic disease burden. ctDNA positivity was associated with a higher frequency of invasive disease and nodal involvement, indicating systemic spread.
- Urinary utDNA: Primarily reflects the local tumor status within the bladder.
- Clinical Significance: In ctDNA-negative patients, utDNA status provides critical supplementary information. “Double negative” patients (both ctDNA and utDNA negative) had the highest likelihood of achieving pCR, whereas “ctDNA-negative but utDNA-positive” patients faced a higher risk of local residual disease (including non-muscle-invasive bladder cancer [NMIBC]).
05. Prognostic Stratification: Complementary Value in Survival Assessment
Regarding EFS, utDNA provided an additional layer of prognostic information beyond ctDNA alone. In the subgroup of patients who were ctDNA-negative prior to surgery, those who were also utDNA-negative had a significantly better prognosis than those who remained utDNA-positive. For ctDNA-positive patients—who often harbor micrometastatic disease or nodal involvement—the added predictive value of utDNA was more limited. Thus, utDNA acts as a vital complement to ctDNA, offering a more comprehensive map of the patient’s disease status from a localized to a systemic level.
06. Conclusion and Outlook: Empowering Bladder-Sparing Clinical Practice
Professor Michiel S. van der Heijden concluded that this dataset—the largest from a Phase III trial describing the association of utDNA with outcomes in MIBC—underscores the profound clinical relevance of utDNA. By providing critical insights into the primary bladder tumor that ctDNA might otherwise miss, utDNA testing could become a pivotal tool in selecting optimal candidates for bladder preservation or optimizing surgical timing based on comprehensive liquid biopsy status.
