BOND/CORE-001: uGDB as a Biomarker for Viral Therapy in Bladder Cancer
Colin P.N. Dinney, MD, PhD, discussed updated analyses of the BOND-003 and CORE-001 trials in bladder cancer.
Colin P.N. Dinney, MD, PhD
Key findings from updated analyses of the BOND-003 and CORE-001 trials (NCT04452591; NCT04387461), presented by Colin P.N. Dinney, MD, PhD, demonstrate the clinical utility of urinary genomic disease burden (uGDB), assessed via the UroAmp platform, in predicting response to cretostimogene grenadenorepvec therapy for bladder cancer.1
The UroAmp assay, a convergent genomic and genetic liquid biopsy, quantifies mutations and DNA alterations in urine tumor DNA to determine minimal residual disease (MRD) status.
Longitudinal assessment demonstrated a strong correlation between MRD status and clinical response. Notably, patients achieving complete responses at 3 and 6 months exhibited a statistically significant reduction in uGDB across both studies, suggesting a durable treatment effect. The observed reduction in uGDB in patients salvaged by reinduction further supports this treatment strategy's value.
The study shows that a longitudinal reduction in uGDB is associated with a favorable response to cretostimogene and a reduced risk of recurrence. These data, as discussed by Dinney, lead study author and chairman of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, may inform future clinical trial designs and provide insights into risk-adapted treatment paradigms for cretostimogene monotherapy and rational combinations.
He further elaborated on these findings in an interview with Targeted OncologyTM.
Targeted OncologyTM: Please explain the primary utility of urinary genomic disease, learning, and evaluating cretostimogene grenadenorepvec?
Dinney: The purpose of the study was to try to identify a biomarker that would help the selection of patients that would best be suited by cretostimogene grenadenorepvec therapy.
How do the updated analyses from BOND-003 and CORE-001 trials correlate to changes in urinary genomic disease burden with cretostimogene grenadenorepvec?
I think the BOND-003 data are more mature. What we found was that the test, UroAmp, is designed to detect the minimal disease burden by the genomic disease burden, which is a percentile ranking of the variant allele frequency of a sample relative to its ranking within the established test set. That helps to characterize the tumor as being MRD positive and high risk, or MRD negative and low risk.
What specific genomic markers or patterns within urinary analysis show the strongest correlation with response to this agent?
UroAmp is a convergent genomic, genetic platform which quantifies mutations and DNA alterations, alterations in urine, tumor DNA. It's a liquid biopsy, and they perform a deep next generation sequencing of a 60-gene, bladder cancer-specific panel, and low pass a whole genome sequencing to identify copy number variants and aneuploidy. So basically, they identify some commonly mutated genes in these patients, as well as aneuploidy, which is aberrant chromosome numbers and then copy number variants. The most common alterations in patients in this study were alterations in mutations in TERT, in p53 in genes coding for the chromatin-modifying proteins and in proliferation pathways. There's also a unique aneuploidy population which represented a high-risk subset of carcinoma in situ which shared a genetic signature with muscle-invasive disease. This was a high genomically altered cohort compared with others in the same space.
What specifically was presented regarding this analysis at AUA 2025?
We wanted to see if the UroAmp would predict response to the drug. At baseline, the UroAmp signature did not predict response. However, at 13 weeks, that is, after the first course of therapy, the urine was able to stratify MRD positive, the high risk of MRD-negative tumors, and that correlated with the complete response rate at 12 months, which was the primary end point. What we found was that in the MRD-positive or high-risk [population], the 12-month recurrence-free survival was only 33%, but in the MRD-negative or low-risk population, it was 76%. We also found that a very remarkable decrease in the MRD in those patients who were reinduced and achieved a complete response. So, this actually emphasizes the benefits of the reinduction for those patients.
How do these findings inform decisions for using this test?
The other thing that we identified was [through] longitudinal studies. We found, over time, that there was a reduction in the prevalence of tumors that had mutations in RB and p53, and we also saw a reduction in that aneuploid population. We are seeing that more aggressive tumors are being killed by the drug. I think that one way to use this would be to use the longitudinal genetic disease burden information in the design of novel trials, to use this information to accelerate or decelerate therapy.
For a community oncologist, what should they take away from this research?
The first thing to recognize is the drug is an oncolytic replicating on COVID adenovirus. In these patients we treated, there are preexisting systemic anti-adenovirus antibodies which don't prevent treatment. Oncologists should know that if you have had patients who have had a common COVID adenovirus, they're not resistant to treatment. There's no evidence. And in fact, with people who respond, the antibody titers go up. There's no evidence that neutralizing antibodies will inhibit the effect of therapy. It is also very safe. The biomarkers can be used, [and] I think [will], be used in novel trial designs as we move forward.
