This clinical trial studies cognitive function in men with prostate cancer treated with androgen receptor directed therapies such as abiraterone acetate and enzalutamide. The investigators use MRI imaging (non-invasive, non-contrast) to see whether there are changes in brain structure or activity related to treatment that may be related to changes in cognitive function. The investigators are also looking for genetic variations that might make patients more or less sensitive to cognitive changes during treatment for prostate cancer.

PRIMARY OBJECTIVES:

I. To compare cognitive function and associated mediators of cognitive function (quality of life, depression, pain, and fatigue) of men with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone sensitive prostate cancer during treatment with enzalutamide (mCRPC only) and abiraterone acetate (mHSPC or mCRPC).

SECONDARY OBJECTIVES:

I. To identify characteristics of men with mCRPC associated with change in cognitive function during treatment with androgen receptor (AR) directed therapy.

II. To compare quality of life and associated factors, including fatigue, pain, and depression, of men with mCRPC during treatment with enzalutamide and abiraterone acetate.

TERTIARY OBJECTIVES:

I. To analyze whether single nucleotide polymorphisms (SNPs) may be associated with change in cognitive function during treatment with AR directed therapy.

II. To compare the functional and structural components of the brain over time and between the brains of men with mCRPC treated with enzalutamide or abiraterone acetate using diffusion tensor imaging (DTI), functional MRI (fMRI), arterial spin labeling (ASL), and other advanced neuroimaging techniques.

OUTLINE: Treatment patients with metastatic castration-resistant prostate cancer are randomized to 1 of 2 arms. Control patients receiving long term androgen deprivation therapy will be assessed with the same measures as a control arm.

ARM I: Patients receive standard of care treatment with gonadotrophin releasing hormone (GnRH) agonist/antagonist therapy. Patients also receive abiraterone acetate orally (PO) and prednisone PO twice daily (BID) in the absence of disease progression or unacceptable toxicity. Patients then undergo cognitive assessment comprising of neuro-cognitive tests and assessments of overall quality of life, fatigue, pain, and symptoms at baseline, 3, 6, and 12 months. Patients also undergo MRI program for 40 minutes comprising of DTI, fMRI, ASL MRI, Magnetization Prepared Rapid Gradient Echo (MPRAGE) MRI, Fluid attenuated Inversion Recovery (FLAIR) MRI, and blood oxygenation level-dependent (BOLD) MRI at baseline and 3 months.

ARM II: Patients receive standard of care treatment with GnRH agonist/antagonist therapy. Patients also receive enzalutamide PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo cognitive assessment and MRI program as in Arm I.

ARM III: Patients receive standard of care treatment with GnRH agonist/antagonist therapy and undergo cognitive assessment and MRI program as in Arm I.

Inclusion Criteria:

• Have diagnosis of prostate cancer and have received treatment with GnRH agonist or antagonist therapy for at least 1 month prior to enrollment.
• Willing and able to complete survey questionnaires in English without assistance through the duration of the study. This stipulation is in place because not all of the proposed quality of life or cognitive tests are available or validated in other languages.
• Age ≥ 18 years.
• Ability to understand and the willingness to sign a written informed consent document written in English that is approved by an institutional review board.
• Have either newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) or castration-resistant metastatic prostate cancer (mCRPC) and eligible to undergo treatment with abiraterone acetate (mHSPC or mCRPC) or enzalutamide (mCRPC)
• Patients may have received the following prior AR directed therapy prior to enrollment: bicalutamide, ketoconazole. Prior to enrollment, patients may have received treatment with abiraterone acetate or enzalutamide for no more than 14 days before completing baseline studies.
• Patients may have received chemotherapy for hormone-sensitive metastatic prostate cancer only, but it must not have lasted for more than 6 months. At least 12 months must have elapsed since completion of chemotherapy.
• Patients may have received prior definitive radiation therapy or surgery. At least 60 days must have elapsed since completion of definitive radiation therapy or surgery and patient must have only grade 2 or less adverse effects at the time of registration. Enrollment during palliative radiation of ≤ 10 days, or radiation of ≤ 10 days during the duration of the study is allowed.
• Patients must be able to take oral medication.

Exclusion Criteria:

• Prior treatment with enzalutamide or abiraterone acetate for > 14 days prior to enrollment and completion of baseline tests.
• Receipt of chemotherapy for prostate or other cancer within the past 12 months with residual cognitive deficits, or receipt of chemotherapy for mCRPC. Patients/physicians planning treatment with chemotherapy during the 12 month period of the investigation are also ineligible.
• History of cognitive impairment or dysfunction, including a history of dementia, Alzheimer's disease, stroke with residual cognitive deficits, cognitive dysfunction related to alcohol or substance abuse, or cognitive dysfunction related to prior treatment for any cancer.
• Patients with a seizure history, history of recurrent falls, or known brain metastases are excluded from this clinical trial because of their poor prognosis and because of their heightened risk of seizure or progressive cognitive and/or neurologic dysfunction that would confound the evaluation.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations/substance abuse that would limit compliance with study requirements.
• Patients with a "currently active" second malignancy other than non-melanoma skin cancers are not eligible. Patients are not considered to have a "currently active" malignancy if they have completed all therapy and are now considered without evidence of disease for 1 year. Patients with cognitive dysfunction related to treatment of another malignancy, including a history of "chemo-brain", are ineligible.
• Patients taking psychotropic medications or illicit drugs that may alter cognition, concentration, or behavior. Appropriate treatment by a licensed provider with medications for depression or anxiety, including but not limited to SSRIs, SNRIs, and standard dose benzodiazepines at a stable dose, is permitted