Study of Enzalutamide With and Without Sorafenib in Advanced Hepatocellular Carcinoma Patients

Inclusion Criteria: * Histologic proof of HCC reviewed and confirmed at per the local standard of care. * Advanced unresectable or metastatic disease * Measurable disease as defined by RECIST version 1.1 * Tissue available for the evaluation of AR by IHC on pretreatment HCC samples. If tissue is not available, a pretreatment biopsy will not be necessary for eligibility * Age ≥ 18 years-old * ECOG performance status ≤ 2 * Child-Pugh category A * Adequate hepatic function defined by: * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x upper limit of normal (ULN) * Total Bilirubin ≤ 1.5 x ULN * Adequate hematologic function defined by: * Absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 10\^9/L) * Platelets ≥ 75,000/mm3 (≥ 75 x 10\^9/L) * Hemoglobin ≥ 8 g/dL (≥ 80 g/L) * Adequate renal function defined by: * Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min (using the Cockcroft-Gault equation) * Patients must be on antiviral therapy per the local standard of care if active or occult hepatitis B (HBV) infection. * Patients with active hepatitis C (HCV) may not be antiviral therapy. * Patients with a history of hypertension should be well controlled (BP ≤ 140/90) on a regimen of antihypertensive therapy. * Gastrointestinal disorders in the opinion of the treating physician that would impair absorption. * Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study. * Patients with history of liver transplantation may be eligible for the dose expansion cohorts (Parts 2A and 2B) of this study provided all eligibility criteria are met and provided the subject has not had any episodes of acute rejection or serious opportunistic infection within 3 months from enrollment. * Female subjects of childbearing potential must not be pregnant or lactating at screening. * Participants must be capable of understanding and complying with the protocol requirements and signing informed consent. * Certain immunosuppressive agents such as tacrolimus and sirolimus are prohibited due to drug interaction risk thus liver transplant patients who require these medications for immunosuppression are not eligible. * Patients receiving everolimus at immunosuppressive dosages are eligible since the everolimus doses used are lower than standard anti-neoplastic dosages and this agent does not demonstrate anti-cancer activity in HCC. Everolimus does not interact adversely like other immunosuppressive agents. Exclusion Criteria: * Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma * For patients who will receive enzalutamide monotherapy, failure or intolerance of prior sorafenib is required for enrollment. For patients who will receive combination therapy, prior sorafenib is excluded. * Patients may not have received cytotoxic, biologic or small molecule kinase inhibitor systemic therapy f or at least 3 weeks prior to the first dose of study treatment. * Patients must not have received prior regional therapy such as ablation, embolization, or radiation therapy for at least 2 weeks prior to the first dose of study treatment. Patients who receive such therapy should have evidence of radiologic progression at this site or other progressing measurable disease. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before study enrollment. Eligible subjects must be without corticosteroid treatment at the time of study enrollment. * History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with antiepileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months of enrollment. * Clinically significant cardiovascular disease including: * Myocardial infarction within six months prior to Screening; * Uncontrolled angina within three months prior to Screening; * Congestive heart failure NYHA class 3 or 4, or subjects with history of congestive heart * failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or MUGA scan * performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%; * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes); * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; * Anticoagulation with warfarin * Inability to swallow tablets * Subjects with history of another primary cancer, with the exception of: * curatively resected non-melanoma skin cancer; * curatively treated cervical carcinoma in situ; * other primary solid tumor with no known active disease present in the opinion of the investigator will not affect patient outcome in the setting of current HCC. * Patients who are on strong inhibitors of CYP2C8, strong or moderate inducers of CY3A4 and CYP2C8 should discontinue these medications 2 weeks prior to the start of treatment