Molecular Features and Pathways in Predicting Drug Resistance in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Enzalutamide

PRIMARY OBJECTIVES:

I. To assess the correlations between baseline molecular features and pathways and
prostate-specific antigen (PSA) response (= 50% decline) at 12 weeks versus (vs.)
baseline.

SECONDARY OBJECTIVES:

I. To assess the correlations between the baseline molecular features and pathways and
progression-free survival (defined as time from day 1 of study drug treatment to date of
radiographic progression or clinical progression), disease-specific survival (defined as the
time from day 1 of study drug to date of death from prostate cancer), and overall survival
(defined as time from day 1 of study drug treatment to date of death from any cause).

II. To assess the correlations between the baseline molecular features and pathways and time
to PSA progression.

III. To identify molecular features and cellular pathways present in tumors from men with
metastatic castrate-resistant prostate cancer (CRPC) that are progressing despite
enzalutamide treatment.

IV. To explore correlation between baseline molecular features and pathways and objective
response.

V. To assess the correlations between the baseline molecular features and pathways and degree
of PSA decline at 12 weeks and maximal PSA decline observed while on study.

VI. To assess the correlations between the baseline molecular features and time on treatment.

TERTIARY OBJECTIVES:

I. To assess correlations between cell-free deoxyribonucleic acid (cfDNA) molecular features
from blood and molecular features and pathways from the biopsy samples.

II. To assess correlations between cfDNA molecular features and endpoints in the primary and
secondary objectives listed above.

III. To explore correlations with baseline molecular features and tissue histology.

IV. To explore correlations with baseline tissue histology and PSA change, time to PSA
progression, time on treatment, progression-free survival, and overall survival.

OUTLINE:

Patients undergo collection of blood and tissue samples at baseline, during administration of
enzalutamide, and after the time of disease progression for analysis via
immunohistochemistry, comparative genome hybridization, and sequencing.

After completion of study, patients are followed up every 12 weeks.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features

- Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH)
analogue or orchiectomy (i.e., surgical or medical castration); for patients who have
not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue
therapy for the duration of the trial

- Radiographic evidence of regional or distant metastases with suspected tumor in an
area that is safe to biopsy

- Willingness to undergo a tumor biopsy at baseline and at disease progression

- Serum testosterone level < 50 ng/dL at screening

- Progressive disease by PSA or imaging in the setting of medical or surgical
castration; disease progression for study entry is defined as one or more of the
following three criteria:

- PSA progression defined by a minimum of three rising PSA levels with an interval
of >= 1 week between each determination; the PSA value at screening should be >=
2 ug/L (2 ng/ml)

- Soft tissue disease progression defined by Response Evaluation Criteria in Solid
Tumors (RECIST 1.1)

- Bone disease progression defined by two or more new lesions on bone scan

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

- Clinically able, in the opinion of the investigator, to receive MDV3100 (enzalutamide)

- Willing and able to give informed consent

- A minimum of 4 weeks elapsed off of anti-androgen therapy prior to enrollment for
flutamide and 6 weeks for bicalutamide and nilutamide without evidence of an
anti-androgen withdrawal response; patients who NEVER HAD A PSA decline with the most
recent anti-androgen therapy or in whom the response to the most recent anti-androgen
was for < 3 months require only a 2 week washout period prior to first dose of study
drug

Exclusion Criteria:

- Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
investigator, would make the patient inappropriate for enrollment

- Metastases in the brain or active epidural disease (NOTE: patients with treated
epidural disease are allowed)

- Platelet count < 75,000/uL

- Prothrombin time (PT) or international normalized ratio (INR) and a partial
thromboplastin time PTT > 1.5 times the institutional upper limit of normal (ULN)

- Structurally unstable bone lesions suggesting impending fracture

- Previous treatment with MDV3100, ARN-509, or BMS-641988

- Medical contraindications to stopping aspirin, Coumadin or other anticoagulants for 1
week prior to image-guided tumor biopsies

- Plans to initiate treatment with an investigational agent while on study prior to
discontinuation of MDV3100 treatment

- A second active malignancy except adequately treated non-melanoma skin cancer or other
non-invasive or in situ neoplasm