Cognitive Effects of Androgen Receptor Directed Therapies for Advanced 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