Integrated Genotypic, Phenotypic and Immunologic Analysis of Ethnically Diverse Prostate Cancers

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Project Summary Abstract Prostate cancer is the leading cause of cancer-related death among men in the United States, and its incidence and mortality rate is markedly higher in African-American men than in non-Hispanic White men and Asian men. Although socio-economic status and other environmental and cultural factors contribute to this disparity, emerging evidence indicates that genetic factors also play critical roles. This proposal seeks to add correlative studies to an ongoing clinical trial of an ethnically diverse cohort of men undergoing treatment for metastatic prostate cancer with the PARP inhibitor talazoparib plus standard first-line hormone therapy with androgen deprivation therapy plus abiraterone. A key aspect of the clinical trial design is to enrich recruitment of minority subjects, who have been under-represented in the critical trials that defined current first-line therapy. The target accrual is 70 subjects, with 30% intended to be African-American and 30% Asian-American. This is important because these groups have highly divergent lengths of triplicate repeats in the androgen receptor (AR), which impacts the function of AR and could thus impact depth or duration of response to AR targeted therapy The objective of this proposal is to leverage biospecimens collected as part of this already funded, ongoing trial to conduct correlative studies that will identify biomarkers of patients who benefit most from the treatment, We will: 1) determine in a diverse population of prostate cancer patients how genomic alterations are associated with treatment outcomes, and how they evolve upon cancer progression; 2) integrate the genomic findings with profiling of AR triplicate repeats and Wnt/Myc signaling to understand how these are distributed among different ethnic groups; and 3) utilize digital spatial pathology to describe the adaptive immune response in the primary tumor and measure any associations with genomic features, AR repeats, and response to treatment. This uniquely diverse population of prostate cancer patients will create a critical resource to study differences in tumor biology and host response. Tissue genomics as well as ctDNA analysis will be performed using commercial CLIA-certified assays. Furthermore, this study will generate extremely novel data using digital spatial pathology to describe immune infiltration and how infiltration interacts with tumor response. These data will culminate in an integrated analysis of how genomic alterations compare or are complementary with AR variations, Wnt/Myc signaling, and tumor immune infiltration and help to define molecular characteristics of responsive populations—ultimately leading to better patient outcome through improved treatment options.