LHRH Analogue Therapy With Enzalutamide or Bicalutamide in Treating Patients With Metastatic Hormone Sensitive Prostate Cancer

PRIMARY OBJECTIVES:

I. To compare the rates of achieving prostate-specific antigen (PSA) remission at month 7
with LHRH analogue therapy and enzalutamide (Arm A) with that achieved with LHRH analogue and
bicalutamide (Arm B) in metastatic hormone sensitive prostate cancer.

SECONDARY OBJECTIVES:

I. To compare the primary endpoint by race. II. To compare the rates of each of 2 types of
response by treatment arm: measurable disease response; and PSA response.

III. To compare each of 7 time-to-event endpoints by treatment arm: duration of overall
response (RD); duration of stable disease (SDD); time to treatment failure (TTF);
time-to-progression (TTP); TTP in patients with bone metastases; progression-free survival
(PFS); and overall survival (OS).

IV. To compare the rates of each type of toxicity by treatment arm. V. To compare the
incidence rate of skeletal related events (SRE), and the time until SRE, separately by
treatment arm.

VI. To compare the rates of circulating tumor cell (CTC) response by treatment arm.

VIII. To explore the molecular mechanisms within the androgen receptor pathway by determining
the levels of chemokine (C-X-C motif) receptor 4 (CXCR4) and transmembrane protease, serine 2
(TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) expression, androgen
metabolism enzymes; androgen receptor variants, and length of cytosine-adenine-guanine (CAG)
repeats within the androgen receptor gene, and to associate them with the primary endpoint.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive enzalutamide orally (PO) once daily (QD) and undergo orchiectomy or
receive LHRH analogue therapy (leuprolide acetate, goserelin acetate, or any other Food and
Drug Administration [FDA] approved preparation). Treatment continues in the absence of
disease progression or unacceptable toxicity.

ARM B: Patients receive bicalutamide PO QD and undergo orchiectomy or receive LHRH analogue
therapy as in Arm A. Treatment continues in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Histologically confirmed prostate adenocarcinoma with metastasis either starting or
recently started on LHRH analogue therapy. [Late induction permitted within 3 months
of starting LHRH analogue therapy or antiandrogen]

- All patients who have not initiated hormone therapy (Early induction patients) must
have elevated PSA ≥ 4 ng/ml within 28 days prior to registration. For late induction
registrations, PSA must be ≥ 4 ng/ml prior to start of androgen deprivation therapy;
either antiandrogen or LHRH analogue or GNRH antagonist .If patients are on
antiandrogen, this will need to be discontinued for at least 7 days prior to
registration.

- Patients with a history of prior neoadjuvant or adjuvant hormone therapy are eligible
provided they have received twenty four or less months of hormone treatment (single or
combination treatment, excluding orchiectomy). Both therapies (neoadjuvant/adjuvant
hormone therapy) must have been discontinued at least 6 months prior to registration.
This is intended to exclude patients who might have been rendered indirectly androgen
insensitive.

- There must be no plans to receive concomitant chemotherapy, biological response
modifiers, radiation therapy or hormonal therapy. Concomitant radiation therapy is
allowed for the palliation of severe pain/neuropathic compression. Prior or
concomitant use of megestrol acetate for the treatment of hot flashes is allowed.

- Patients must have a performance status of 0 - 2 by Zubrod Criteria.

- Patients must have recovered from any major infections and/or surgical procedures
and,in the opinion of the investigator, not have significant active medical illness
precluding protocol treatment or survival.

- No prior malignancy is allowed except for adequately treated basal cell (or squamous
cell) skin cancer, superficial or in situ cancer of the bladder. For an invasive
cancer the patients should be disease free for at least 3 years prior to enrollment on
study.

- For all patients a bone scan must be performed within 60 days prior to registration
for tumor assessment. CT scans (abdomen and pelvis) and chest x-ray are optional, but
must be repeated if used for disease assessment. For late induction registrations,
tumor assessment imaging showing metastatic disease must be available prior to start
of androgen deprivation therapy.

- Age 18 or older and willing and able to provide informed consent.

- Willingness to swallow pills and no medical condition that would interfere with this.

- Male patient and his female partner who is of childbearing potential must use 2
acceptable methods of birth control (one of which must include a condom as a barrier
method of contraception) starting at screening and continuing throughout the study
period and for 3 months after final study drug administration. Patients are also
required to use a condom if having sex with a pregnant woman.

- Patient should agree to a tumor tissue biopsy prior to protocol enrollment. Post
therapy biopsy is optional.

- Patients who are being treated with a GNRH antagonist should be willing to switch to a
LHRH analogue after registration.

- Patients must have one of the following a) Low volume disease (defined as no visceral
metastases and < 4 bone metastases) or b) are not candidates for docetaxel based
chemotherapy or 3) refused docetaxel chemotherapy

Exclusion Criteria:

- History of seizure or any condition that may predispose to seizure (e.g., prior
cortical stroke, significant brain trauma) at any time in the past. Also, history of
loss of consciousness or transient ischemic attack within 12 months of Day 1 visit;

- Known or suspected brain metastasis or active leptomeningeal disease;

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

- Absolute neutrophil count < 1,000/μL, or platelet count < 50,000/μL, or hemoglobin<8
g/dL) at the Screening visit.

- Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >
2.5 times the upper limit of normal

- Creatinine > 177 μmol/L (2 mg/dL)

- Clinically significant cardiovascular disease including: Myocardial infarction within
6 months; Uncontrolled angina within 3 months; Congestive heart failure New York Heart
Association (NYHA) class 3 or 4, or patients with history of congestive heart failure
(NYHA) class 3 or 4 in the past, unless screening echocardiogram or multi-gated
acquistion scan performed within 3 months results in a left ventricular ejection
fraction that is greater or equal to 45%; History of clinically significant
ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation,
torsades de pointes); History of Mobitz II second degree or third degree heart block
without a permanent pacemaker in place; Hypotension as indicated by systolic blood
pressure < 86 millimeters of mercury (mmHg) at the Screening visit; Bradycardia as
indicated by a heart rate of < 50 beats per minute on the Screening ECG; Uncontrolled
hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood
pressure > 105 mmHg

- Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer
disease within last 3 months);

- Treatment with concurrent 5-α reductase inhibitors (finasteride, dutasteride),
estrogens, and/or cyproterone

- Treatment with systemic biologic therapy for prostate cancer (other than approved bone
targeted agents and GnRH-analogue therapy) or other agents with anti-tumor activity
within 4 weeks of enrollment (Day 1 visit);

- History of prostate cancer progression on ketoconazole;

- Prior use, or participation in a clinical trial, of an investigational agent that
blocks androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or
agents that block the androgen receptor (e.g.,ARN-509)

- Previous enzalutamide therapy;

- Use of an investigational agent within 2 weeks of enrollment (Day 1 visit);

- Use of herbal products that may have hormonal anti-prostate cancer activity and/or are
known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater
than the equivalent of replacement steroids or > equivalent of 10 mg of prednisone
perday within 4 weeks of enrollment (Day 1 visit);

- Any condition or reason that, in the opinion of the Investigator, interferes with the
ability of the patient to participate in the trial, which places the patient at undue
risk, or complicates the interpretation of safety data.

- Prior chemotherapy for metastatic disease.

- >30 days of antiandrogen therapy monotherapy without androgen deprivation therapy.

- Life expectancy of 6 months or less.