Enzalutamide and Relacorilant in Treating Patients with Metastatic Castration Resistant Prostate Cancer

Inclusion Criteria

• Histologically or cytologically confirmed prostate cancer with documented metastatic disease
• Evidence of castrate testosterone level < 50 ng/dl (or surgical castration)
• Evidence of disease progression: * 2 or more new lesions on bone scan or * Progressive disease on computed tomography (CT)/magnetic resonance imaging (MRI) according to RECIST 1.1 criteria or * Rising PSA: PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart
• Prior treatment with at least one line of potent androgen receptor signaling inhibitor (e.g. abiraterone, enzalutamide, apalutamide) in either castration-sensitive or castration-resistant setting
• Any prior therapy for castrate disease is acceptable except prior GR antagonist treatment (e.g. mifepristone or relacorilant)
• Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug
• Denosumab or zoledronic acid are allowed
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Total bilirubin =< 1.5 x the upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Albumin >= 3.0 g/dL
• Platelet count (plt) >= 80,000 /uL
• Hemoglobin (Hgb) >= 9 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, or 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 other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart), or any herbal product known to decrease PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid within 2 weeks prior to first dose of study drug * Patients who have been on systemic corticosteroids with prednisone equivalent of 10 mg or greater for greater than 3 months immediately prior to participation in this study must have documented ability to tolerate cessation of corticosteroids prior to enrollment
• Inability to swallow capsules or known gastrointestinal malabsorption
• Evidence of visceral disease on imaging in a patient who is an appropriate candidate for and has not received cytotoxic chemotherapy (docetaxel or cabazitaxel)
• History of other malignancies, with the exception of: adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 malignancies who 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
• Documented history of or current brain metastases due to seizure risk
• Serious intercurrent 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