Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC

Major Inclusion Criteria: * Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures, and provide written informed consent * Males ≥18 years of age at the time of signing consent * Histologically confirmed adenocarcinoma of the prostate with metastatic disease * Dose-Determination Phase Segment 1 and Expansion Phase: Progressive disease as defined by PSA or imaging after most recent prior therapy. PSA ≥1 ng/mL, if a confirmed rise in PSA is the only indication of progression. Progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy. * Dose-Determination Phase Segment 2: Currently receiving enzalutamide with a rising PSA as follows: 1. Rising PSA: 25% increase over nadir and an absolute value of \>1 ng/mL by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy. 2. Patients must have received enzalutamide for a minimum of 12 weeks and be on stable doses of enzalutamide ≥80 mg QD for at least 4 weeks prior to Cycle 1 Day 1. Patients will continue enzalutamide without interruption during the Screening Period (no wash-out period). This will be the enzalutamide starting dose for combination with CORT125281 beginning on Cycle 1 Day 1. 3. M0 disease is allowed * Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy as follows: 1. Abi-Resistant Cohort: Patients must have progressed during treatment with abiraterone. 2. ARant-Resistant Cohort: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide. These patients will continue enzalutamide without interruption during the Screening Period (no wash-out period required). * Baseline tumor assessment performed within 28 days prior to the first dose of study treatment (CORT125281 and/or on-study enzalutamide, whichever is earliest) * Prior surgical or chemical castration with serum testosterone \<1.7 nmol/L (50 ng/dL). If the method of castration is use of a luteinizing hormone releasing hormone (LHRH) analogue,there must be a plan to maintain effective LHRH analogue treatment for the duration of the trial * Consent to have all protocol required pharmacodynamic biomarker samples, including the pretreatment and on treatment paired tumor biopsies (mandatory for a subset of patients). * Consent to provide mandatory pharmacogenomic blood sample (Dose-Determination Segment 1 only) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate baseline organ function within 14 days prior to the first dose of study treatment (on-study enzalutamide and/or CORT125281, whichever is earliest) * Patients receiving systemic corticosteroids greater than 2-weeks in duration within 3 months of study entry or with clinical evidence of adrenal insufficiency must have evidence of adequate adrenal function based upon morning plasma cortisol concentration or ACTH (cosyntropin) stimulation test * If a patient engages in sexual intercourse with a woman of childbearing potential, a condom with spermicide and another form of birth control must be used during and for 100 days after the final dose of study treatment (CORT125281 or enzalutamide, whichever is latest). A condom is required during and for 100 days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least 100 days after the final treatment administration. Major Exclusion Criteria: * Received chemotherapy, non-palliative radiotherapy, immunotherapy, or any investigational cancer therapies within 21 days prior to the first dose of CORT125281, or treatment with such therapies is planned during protocol treatment. Concomitant anticancer therapy is not permitted during the enzalutamide Lead-in Period during Dose-Determination Phase Segment 1 * More than two prior cytotoxic chemotherapy regimens for the treatment of mCRPC Dose Determination Phase and Expansion Phases will exclude patients for the following: * Dose-Determination Phase (Segment 1 only) * Progressed during treatment with enzalutamide prior to Cycle 1 Day -28 (only applies to patients receiving enzalutamide Lead-in) or * Received prior 2nd generation anti-androgen and require urgent disease response or stabilization * Expansion Phase Abi-Resistant Cohort: * Received prior treatment with enzalutamide, or * Received prior 2nd generation anti-androgen and require urgent disease response or stabilization * Expansion Phase ARant-Resistant Cohort: Require urgent disease response or stabilization * Ongoing or anticipated therapy with hormone therapy (other than LHRH analogue), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within 28 days prior to the first dose of CORT125281 * Contraindication or precaution for enzalutamide * Parenchymal brain metastases * Any clinically significant uncontrolled condition that may increase the risk to the study patient or that the Investigator considers places the patient at unacceptable risk * Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity (e.g., saw palmetto, PC-SPES, PC- HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 28 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study * Received systemic glucocorticoids within 21 days prior to the first dose of CORT125281, or requirement for chronic or frequently used systemic or inhaled glucocorticoids for medical conditions (e.g., rheumatoid arthritis, immunosuppression after organ transplantation). Short courses (\<5 days) for non-cancer related reasons are allowed if clinically required (such as prophylaxis for CT). * Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 or with sensitive substrates of CYP3A4, CYP2C9 or CYP2C19