The primary objective of this study is to compare the progression free survival (PFS) of patients with metastatic castration-resistant prostate cancer treated with enzalutamide in combination with LY2157299 (Arm 1) versus enzalutamide alone (Arm 2).

Inclusion Criteria:

• Have metastatic castration-resistant prostate cancer
• Must have had prior abiraterone treatment
• Life expectancy of greater than 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 2
• Age ≥18 years
• Have measurable disease
• Patients acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator).
• Ability to take oral medication
• Patients must have adequate organ and marrow function defined by study-specified laboratory tests
• Must use acceptable form of birth control while on study
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Known history or evidence of brain metastases
• Prior chemotherapy for metastatic disease in castration-resistant prostate cancer
• Had surgery within 4 weeks prior to the first dose of study drug
• Had radiation, biological, or other investigational cancer therapy within 2 weeks prior to the first dose of study drug
• Had second-line hormonal therapy within 2 weeks prior to the first dose of study drug
• Systemic steroids within 1 weeks prior to the first dose of study drug
• Had prior enzalutamide, ARN-509, or galeterone therapy
• Have moderate or severe cardiovascular disease
• Have a history of a seizure
• Have uncontrolled intercurrent illness, including but not limited to ongoing or active infection, systematic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric condition that would limit compliance with study requirements
• Have a history of any autoimmune disease:inflammatory bowel disease, (including ulcerative colitis and Crohn's Disease), rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythmatosus (SLE) autoimmune vasculitis (e.g., Wegener's Granulomatosis), central nervous system (CNS) or motor neuropathy considered to be of autoimmune origin (e.g., Guillian-Barre Syndrome, Myasthenia Gravis, Multiple Sclerosis)
• Have known history of infection with HIV, hepatitis B, or hepatitis C