This study will develop a first-in-man CTC-based molecular taxonomy of CRPC in the context of novel AR-directed therapies, categorize different patterns of resistance in this disease setting, and describe their evolution over time and treatment.
The study will construct a multi-center clinical database of men before and after treatment with abiraterone acetate, enzalutamide, and taxane chemotherapy, and will comprehensively analyze CTC DNA for copy gains/losses and whole exome sequencing for acquired mutations, CTC RNA for AR-variants and evidence of epithelial plasticity, and plasma circulating tumor DNA (ctDNA) for whole exome sequencing. Significantly, the investigators will pair the presence of key proposed circulating biomarkers of treatment resistance with patient outcomes on these systemic therapies for the purpose of developing predictive biomarkers that may have direct clinical utility in guiding choice of therapies. It is proposed that specific AR-v's (i.e. AR-v7), biomarkers of epithelial plasticity, and microtubule interacting protein variants will convey docetaxel resistance and be enriched in men failing abiraterone acetate or enzalutamide, while other AR genomic events (AR amplification, AR-v567es, AR mutations, GR overexpression) will be responsive to taxane chemotherapy. This work represents a first-in-field comprehensive analysis of CTC molecular profiles for the development of a CTC molecular taxonomy of mCRPC.
Study Type
OBSERVATIONAL
Enrollment
120
University of Chicago
Chicago, Illinois, United States
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
Weill Medical College of Cornell University
New York, New York, United States
Comparison of median progression free survival (PFS) to AR-v7 status
Time frame: 2 years
Determine the prevalence of defined categories of a molecular taxonomy of mCRPC using CTC biomarkers and correlate each to clinical benefit (PSA response, PFS)
Time frame: 4 years
Compare levels of circulating epithelial to mesenchymal transition (EMT) and other epithelial plasticity (EP) biomarkers with mCRPC taxonomic categories and clinical outcomes (PSA decline rates, PFS)
Time frame: 4 years
Determine molecular lesions in CTCs and ctDNA that consistently emerge during enzalutamide and taxane chemotherapy progression in men with mCRPC
Time frame: 4 years
Correlate specific AR-v7 assays with clinical outcomes (PSA decline rates, PFS)
Time frame: 4 years
Correlatate other AR-variants with clinical outcomes (PSA decline rates, PFS)
Time frame: 4 years
Change in neuroendocrine biomarkers during enzalutamide and taxane progression in men with mCRPC
Time frame: 4 years
Associate high CTC heterogeneity with PFS, OS, and CTC genotype/phenotypes
Time frame: 4 years
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Duke University
Durham, North Carolina, United States