Background: The common germline variant HSD3B1(1245C) encodes for a gain-of-function in 3βHSD1 which is associated with a shorter duration of response to androgen deprivation therapy (ADT) and more rapid disease progression to castration resistant PCa (CRPC) as shown previously in 5 independent cohorts. Therefore, evaluating the effect of such genotype variation on the level of steroid metabolites and the intratumoral dihydrotestosterone (DHT) concentration in benign and tumor tissue of men on ADT is of significant importance. We hypothesize that patients with homozygous HSD3B1 (1245C) genotype (HZ) will have a sustained androgen synthesis from extragonadal precursor steroids and higher concentrations of DHT compared to patients with wild-type HSD3B1 (1245A) (WT) inheritance in the context of testosterone suppression. In addition, it is expected that heterozygous HSD3B1 (1245C) patients (HTZ) will have intermediate levels of DHT. We also hypothesize that treatment with androgen receptor (AR) antagonist (apalutamide) will reverse the effects of elevated DHT on AR signaling in benign and malignant prostate tissue. Methods: In this Phase II trial (NCT02770391), men with newly diagnosed intermediate or high-risk PCa (GS ≥ 4+3, ≥cT2b, or PSA ≥ 10) who are scheduled to undergo radical prostatectomy (RP) will be enrolled into 3 groups based on their HSD3B1 genotype. All pts will receive one dose of 7.5 mg leuprolide injection and apalutamide 240 mg/day orally for 28 ± 3 days prior to RP. DHT and 7 other androgens (including testosterone, Dehydroepiandrosterone, Androstenedione) will be evaluated in the normal and malignant prostate tissue as well as serum samples obtained at the time of RP. AR regulated genes expression (including PSA, FKBP5, TMPRSS2) will be compared across 3 genotypes. A sample size of 57 pts (WT = 30, HTZ = 15, HZ = 12) will allow a statistical power of > 80% (with two-sided α = 0.05) to detect a 4-fold trend in DHT concentrations in the resected prostate tissue (primary endpoint) as well as similar trend in other androgens (secondary endpoint). As of Oct 2017, 16 of planned 57 pts have been enrolled. Clinical trial information: NCT02770391