Apalutamide in Treating Patients With Prostate Cancer Who Are in Active Surveillance

PRIMARY OBJECTIVES:

I. Determine the negative repeat biopsy rate by site directed and systematic prostate biopsy
after 90-days of apalutamide.

SECONDARY OBJECTIVES:

I. Determine the rate of exit at 2 years from active surveillance due to pathologic
reclassification.

II. Determine the overall rate of exit at 2 years from active surveillance.

III. Determine the rate of local treatment (e.g. radical prostatectomy, radiation therapy,
brachytherapy) at 2 years and the local treatment free survival.

IV. Determine prostate-specific antigen (PSA) progression rates and PSA progression free
survival (PFS), as defined by the Prostate Cancer Working Group 2 (PCWG2) criteria.

V. Determine the rate of radiographic disappearance of magnetic resonance imaging (MRI)
detectable prostate cancer following treatment (only in patients with a baseline nodule that
is Prostate Imaging Reporting and Data System [PIRADS] 3 or more and > 5 mm).

VI. Investigate the safety of apalutamide in men undergoing active surveillance; safety will
be evaluated by the incidence, severity, duration, causality, seriousness, and type(s) of
adverse events as assessed by the revised National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), version 4.03 published 14 June 2010.

VII. Track quality of life utilizing the Functional Assessment of Cancer Therapy-Prostate
(FACT-P) and Short Form (SF)36 surveys for each cohort.

VIII. Exploratory biomarker assessment.

OUTLINE:

Patients receive apalutamide orally (PO) once daily (QD) for 90 days.

After completion of the study treatment, patients are followed up at 180, 365, 545, and 730
days.

Inclusion Criteria:

- Have signed an informed consent document

- Be willing/able to adhere to the prohibitions and restrictions specified in this
protocol

- Written authorization for use and release of health and research study information has
been obtained

- Life expectancy >= 10 years (as determined by the treating physician)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Histologically confirmed adenocarcinoma of the prostate as documented by a minimum 12
core prostate biopsy completed within 1-year of enrollment (note: most recent prostate
biopsy must have demonstrated prostatic adenocarcinoma)

- Favorable risk prostate cancer as defined by:

- Very low-risk:

- Clinical stage T1c disease

- PSA density (PSAD) < 0.15 ng/mL

- Gleason score 6

- =< 2 core biopsies with =< 50% involvement of any biopsy core with cancer,
or unilateral disease =< 2 core biopsies with any percentage involvement OR

- Low risk:

- Clinical stage =< T2a

- PSA < 15 ng/mL

- Gleason score 6 OR

- Low-intermediate risk:

- Clinical stage T1c

- PSA < 15 ng/ml

- Gleason 3+4 present in =< 50% of one core/site as detected by systematic
biopsy or MRI/transrectal ultrasound (TRUS) fusion guided biopsy

- Gleason 6 disease in all other cores / sites

- Willing and qualified for active surveillance at Johns Hopkins or the University of
Washington

- Serum testosterone >= 150 ng/dL

- Able to swallow the study drugs whole as a tablet

- Hemoglobin >= 9.0 g/dL, (at screening), independent of transfusion and/or growth
factors within 3 months prior to randomization

- Platelet count >= 100,000 x 10^9/uL (at screening) independent of transfusion and/or
growth factors within 3 months prior to randomization

- Serum albumin >= 3.0 g/dL (at screening)

- Glomerular filtration rate (GFR) >= 45 mL/min (at screening)

- Serum potassium >= 3.5 mmol/L (at screening)

- Serum total bilirubin =< 1.5 x upper limit of normal (ULN) (at screening) (note: in
subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct
and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be
eligible)

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 × ULN (at
screening)

- Medications known to lower the seizure threshold must be discontinued or substituted
at least 4 weeks prior to study entry

- Agrees to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agrees to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 3 months following the last dose of study drug; must also agree not to donate
sperm during the study and for 3 months after receiving the last dose of study drug

Exclusion Criteria:

- Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation
therapy, brachytherapy)

- Prior use of ARN-509 (apalutamide)

- Have known allergies, hypersensitivity, or intolerance to ARN-509 (apalutamide) or its
excipients

- Prior or ongoing systemic therapy for prostate cancer including, but not limited to:

- Hormonal therapy (e.g. leuprolide, goserelin, triptorelin)

- Cytochrome P450 (CYP)-17 inhibitors (e.g. abiraterone, ketoconazole)

- Antiandrogens (e.g. bicalutamide, nilutamide)

- Second generation antiandrogens (e.g. enzalutamide)

- Immunotherapy (e.g. sipuleucel-T, ipilimumab)

- Chemotherapy (e.g. docetaxel, cabazitaxel)

- Have any condition that, in the opinion of the investigator, would compromise the
well-being of the subject or the study or prevent the subject from meeting or
performing study requirements

- History of any of the following:

- Seizure or known condition that may pre-dispose to seizure (including but not
limited to prior stroke, transient ischemic attack, loss of consciousness within
1 year prior to randomization, brain arteriovenous malformation; or intracranial
masses such as schwannomas and meningiomas that are causing edema or mass effect)

- Severe or unstable angina, myocardial infarction, symptomatic congestive heart
failure, arterial or venous thromboembolic events (e.g., pulmonary embolism,
cerebrovascular accident including transient ischemic attacks), or clinically
significant ventricular arrhythmias within 6 months prior to randomization

- Any condition that in the opinion of the investigator, would preclude
participation in this study

- Current evidence of any of the following:

- Uncontrolled hypertension

- Gastrointestinal disorder affecting absorption

- Active infection (e.g. human immunodeficiency virus [HIV] or viral hepatitis) or
other medical condition that would make prednisone/prednisolone (corticosteroid)
use contraindicated

- Any condition that in the opinion of the investigator, would preclude
participation in this study

- The use of drugs known to lower the seizure threshold, including: atypical
antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone), bupropion,
lithium, meperidine, pethidine, phenothiazine antipsychotics (e.g. chlorpromazine,
mesoridazine, thioridazine), and tricyclic antidepressants (e.g. amitriptyline,
desipramine, doxepin, imipramine, maprotiline, mirtazapine)

- The use of strong CYP3A4 inhibitors, including: itraconazole, clarithromycin,
erythromycin, diltiazem, verapamil, delavirdine, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice (or
grapefruits)

- Note: If a patient is on a strong CYP3A4 inhibitor, they can be reconsidered for
enrollment if they can safely stop said medication; a two week or 5 half-lives,
whichever is longer, washout will be required prior to enrolling on study;
subject may not resume medication while receiving apalutamide

- Strong CYP3A4 inducers, including: phenytoin, carbamazepine, rifampin, rifabutin,
rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort

**Note: If a patient is on a strong CYP3A4 inhibitor, they can be reconsidered for
enrollment if they can safely stop said medication; a two week or 5 half-lives,
whichever is longer, washout will be required prior to enrolling on study; subject may
not resume medication while receiving apalutamide

- Any psychological, familial, sociological, or geographical condition that could
potentially interfere with compliance with the study protocol and follow-up schedule