Interactions of Androgen Production, Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer

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Project Summary: We have identified a collective series of factors that affect variability in the production, uptake and conversion of androgens capable of activating the androgen receptor and driving tumor progression in prostate cancer. Paradoxically, however, these same factors may predict response to specific therapies that target these mechanisms. We hypothesize that genetic variation in HSD3B1, SLCO2B1, and SRD5A2, each critical drivers of androgen production, uptake and conversion (APUC) in prostate cancer, confer cumulative effects on outcome in populations determining both high and low likelihoods of response to AR directed agents, and can form effective biomarker-based therapy selection approaches in the context of treatment resistance. Following successful development of both enzalutamide and abiraterone (led by the PI of this proposal) in chemotherapy naïve CRPC, members of our team designed and completed A031201 a randomized phase III NCI Cooperative Group trial of Enzalutamide (E) vs Enzalutamide+Abiraterone Acetate (E/AA). This trial is now complete and the data were recently presented. Clinical and genetic data from nearly all patients affords the opportunity to evaluate outcomes based on HSD3B1, SLCO2B1 and SRD5A genotype, their relationship to disease biology (factors such as wild type versus altered TP53) and clinical outcomes to guide future biomarker-driven treatment science. In this proposal we perform analyses of patient genetic factors and match it to clinical outcome and androgen metabolites based on the APUC model. In the first aim we define the prevalence and magnitude of effect of variants in genetic related to androgen production, uptake and conversion (APUC). Next, we seek to construct a multivariable model to identify “APUC sensitive” and “APUC resistant” profiles integrating disease biological factors known to confer primary and acquired treatment resistance to abiraterone and potentially enzalutamide. Finally, we will test the pharmacodynamic reduction of an abiraterone metabolite, 3-keto 5abiraterone, with agonist capabilities, with the drug Dutasteride in patients who harbor the 1245c variation in the HSD3B1 gene. This variant of HSD3B1 leads to a gain of function and we hypothesize that the accumulation of this agonist drives resistance to abiraterone. Dutasteride inhibits 5 reductase, and therefore the production of the 5 abiraterone metabolite that functions as an AR agonist. Based on the rPFS data we may propose a phase III clinical trial through the cooperative group mechanisms. We will screen approximately 300 individuals on abiraterone to randomize 100 patients to dutasteride or observation. The study has adequate power to demonstrate a meaningful radiographic progression free survival (rPFS) benefit. We will integrate our APUC model into an understanding of the outcomes of this phase II study.