Enzalutamide Plus Relacorilant with Androgen Deprivation Therapy for the Treatment of Patients with High-Risk Localized Prostate Cancer before Surgery

Inclusion Criteria

• Histologically or cytologically confirmed prostatic adenocarcinoma without primary small cell histology
• 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
• National Comprehensive Cancer Network (NCCN) 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 * Prostate specific antigen (PSA) > 20
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Total serum testosterone ≥ 100 ng/dL
• 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 upper limit of normal [ULN], measure direct and indirect bilirubin. If direct bilirubin is ≤ 1.5 X ULN, the subject may be eligible)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 X institutional upper limit of normal
• Albumin ≥ 3.0 g/dL
• Platelet count (plt) ≥ 100,000/uL
• Hemoglobin (Hgb) ≥ 10 g/dL
• Absolute neutrophil count (ANC) ≥ 1500
• Glomerular filtration rate (GFR) ≥ 30 mL/min
• Ability to understand and the willingness to sign a written informed consent document
• 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
• 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: ** Established use of oral, injected or implanted hormonal method of contraception by the female partner ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner ** Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner ** Tubal ligation in the female partner ** Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy), for more than 6 months

Exclusion Criteria

• 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)
• Inability to swallow capsules or known gastrointestinal malabsorption
• 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
• Blood pressure that is not controlled despite > 2 oral agents (systolic blood pressure [SBP] > 160 and diastolic blood pressure [DBP] > 90 documented during the screening period with no subsequent blood pressure readings > 160/100)
• History of seizure disorder or active use of anticonvulsants. Medications used to treat neuropathic pain such as gabapentin or pregabalin are allowed
• Serious inter-current infections or non-malignant medical illnesses that are uncontrolled
• Active psychiatric illness/social situations that would limit compliance with protocol requirements
• New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)
• Concurrent therapy with strong inhibitors of CYP3A4 or CYP2C8 due to concerning possible drug-drug interactions
• Concurrent therapy with strong inducers of CYP3A4 due to concerning possible drug-drug interactions
• 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