A Study of Enzalutamide Plus the Glucocorticoid Receptor Antagonist Relacorilant Versus Placebo for Patients With High-risk Localized Prostate Cancer

Inclusion Criteria: 1. Histologically or cytologically confirmed prostatic adenocarcinoma without primary small cell histology 2. Localized disease: * Surgical resectability must be documented prior to enrollment * No evidence of distant metastatic disease on abdominopelvic imaging, bone imaging * Enlarged lymph nodes below the iliac bifurcation (clinical stage N1) is allowed * Either cross-sectional abdominopelvic imaging + technetium bone scan or PSMA PET imaging will be acceptable to rule out distant metastatic disease 3. High or very high-risk disease (https://www.nccn.org/professionals/physician\_gls/pdf/prostate.pdf) as defined by having one or more of the following: * Clinical T3a or higher * Histologic Grade Group 4 or 5 * PSA \>20 4. Eastern Cooperative Oncology Group performance status ≤ 1 (Appendix A) 5. Total serum testosterone 100 ng/dL 6. Patients must have normal hepatic function as defined below: * Total bilirubin \<1.5 X the upper limit of normal (note that in subjects with Gilbert's syndrome, if total bilirubin is \>1.5 X ULN, measure direct and indirect bilirubin. If direct bilirubin is ≤1.5 X ULN, the subject may be eligible) * AST(SGOT)/ALT(SGPT) \<2.5 X institutional upper limit of normal * Albumin 3.0 g/dL 7. Patients must have normal bone marrow function as defined below: * Platelet count (plt) 100,000 /L * Hemoglobin (Hgb) 10 g/dL * Absolute neutrophil count (ANC) 1500 8. Patients must have adequate renal function as defined below: • glomerular filtration rate (GFR) 30 mL/min 9. Ability to understand and the willingness to sign a written informed consent document. 10. Patients with active diabetes mellitus on glucose lowering medications are eligible provided they agree to and are able to self-monitor daily blood glucose levels due to potential risk of lowering glucose levels on relacorilant. 11. Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Two acceptable methods of birth control thus include the following: * Condom (barrier method of contraception) AND * One of the following is required: 1. Established use of oral, injected or implanted hormonal method of contraception by the female partner; 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner; 3. Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner; 4. Tubal ligation in the female partner; 5. Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy), for more than 6 months. 3.2 Exclusion Criteria 1. Therapy with ANY hormonal therapy for prostate cancer (prior 5-alpha-reductase inhibitors for benign prostate disease is allowed but must be discontinued prior to study initiation). 2. Inability to swallow capsules or known gastrointestinal malabsorption. 3. History of other malignancies, with the exception of: adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 malignancies that are without evidence of disease, or other cancers curatively treated with no evidence of disease for \> 5 years from enrollment. 4. Blood pressure that is not controlled despite \> 2 oral agents (SBP \>160 and DBP \>90 documented during the screening period with no subsequent blood pressure readings \>160/100). 5. History of seizure disorder or active use of anticonvulsants. Medications used to treat neuropathic pain such as gabapentin or pregabalin are allowed. 6. Serious inter-current infections or non-malignant medical illnesses that are uncontrolled. 7. Active psychiatric illness/social situations that would limit compliance with protocol requirements. 8. New York Heart Association (NYHA) class II, class III, or IV congestive heart failure (any symptomatic heart failure). 9. Concurrent therapy with strong inhibitors of Cytochrome P450 3A4 or CYP2C8 due to concerning possible drug-drug interactions. 10. Concurrent therapy with strong inducers of Cytochrome P450 3A4 due to concerning possible drug-drug interactions. 11. Presence of concurrent medical conditions requiring systemic glucocorticoids for immunosuppression (e.g. autoimmune diseases, organ transplantation) that is active and has required glucocorticoids in the last 6 months.