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

Eligibility 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:
• 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.