Inclusion Criteria:  Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma. Evidence of castration-resistant prostate cancer (CRPC). Presence of metastatic disease at study entry documented by 1 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI. Naïve to second generation anti-androgens. Evidence of progressive disease defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy or history of bilateral orchiectomy, with castrate level testosterone. Serum testosterone ≤1.73 nmol/L (50 ng/dL). Subjects receiving bisphosphonates or other approved bone-targeting therapy (e.g., denosumab) must be on a stable dose for at least 28 days prior to the start of study treatment. Demonstrate adequate organ function.  Exclusion Criteria:  Biologic anti-cancer therapy within 28 days prior to the start of study treatment. Use of hormonal agents with anti-tumor activity against prostate cancer within 28 days prior to the start of study treatment. Use of herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 28 days prior to the start of study treatment or plans to initiate during the study. Intervention with any chemotherapy, investigational agents, or other anti-cancer drugs within 28 days of the first dose of study treatment. Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study treatment. Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study treatment. Received a blood transfusion within 28 days of hematologic screening labs. Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 28 days before signing of informed consent. Spinal cord compression. Diagnosis of another clinically significant malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma and other in situ or non-invasive malignancies. Gastrointestinal issues affecting absorption. Significant cardiovascular disease. Known history of seizure or conditions that may pre-dispose them to seizure, including brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Concurrent disease or any clinically significant abnormality. Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide. Use of compounds known to be strong inducers and strong inhibitors of CYP3A and CYP2C8 within 14 days of the first dose of study drug. Use of narrow therapeutic index sensitive CYP2C8 or sensitive substrates for CYP3A and CYP2B6. Use of granulocyte colony stimulating factor within 7 days prior to screening laboratories.