Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in advanced prostate cancer, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 47 polymorphisms (PMs) in 22 genes involved in the androgen metabolic pathway were investigated using tagging SNPs for association with time to onset of castration resistance in 144 Caucasian men diagnosed with advanced prostate cancer undergoing ADT. Linear regression was employed using Gleason score as a covariate and assessing each SNP under one of three genetic models: 1) an additive model in which the number of minor alleles contributes increasing risk (or protection), 2) a dominant model in which the presence of 1 or 2 minor alleles have the same effect, and 3) a recessive model in which the presence of 2 minor alleles are necessary. Results: PMs in 3 genes (CYP1A1, HSD17B3, and HSD17B12) were significantly associated with time to prostate cancer recurrence after medical castration while controlling for Gleason Score. Table summarizes the genes found to be significantly associated with time to recurrence and the modes of inheritance considered. (Only SNPs found to be nominally significant (p < .05) either with or without controlling for Gleason score in at least one model are shown.) Conclusions: In this preliminary report of ongoing work, germ line variations in multiple genes in the sex steroid hormone metabolic pathway predicted time to response to ADT, and warrant further validation to define their role as prognostic and predictive markers in this setting.

*Increased time to failure. ^Decreased time to failure.