Enzalutamide, Radiation Therapy and Hormone Therapy in Treating Patients With Intermediate or High-Risk Prostate Cancer

PRIMARY OBJECTIVE:

1) To assess the safety of the combination of neoadjuvant and concurrent enzalutamide with an
luteinizing-hormone-releasing hormone (LHRH) agonist and radiation therapy.

SECONDARY OBJECTIVES:

1. To determine the efficacy of the combination of enzalutamide with an LHRH agonist and
radiation therapy using prostate specific antigen (PSA) kinetics.

2. To determine the efficacy of the combination of enzalutamide with an LHRH agonist and
radiation therapy using PSA nadir.

3. To describe patient-reported outcomes including: Expanded Prostate Cancer Index
Composite (EPIC), American Urological Association (AUA) Symptom Index, PROstate magnetic
resonance (MR) Imaging Study (PROMIS) Fatigue Scale.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) for 6 months. Beginning 2 weeks
after start of enzalutamide, patients receive LHRH agonist therapy with goserelin acetate
subcutaneously (SC) or leuprolide acetate intramuscularly (IM) or SC for 6 months
(intermediate risk patients) or 24 months (high risk patients) post-radiation therapy.
Beginning 8 weeks after the start of LHRH agonist therapy, patients undergo either intensity
modulated radiation therapy (IMRT) or volumetric arc therapy (VMAT) daily five days a week
for 8 weeks.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

1. Prostate adenocarcinoma without distant metastatic disease with either Gleason score ≥
7, PSA ≥ 10 ng/ml, or T2b or greater disease

2. Age > 18

3. Performance Status: ECOG 0-1

4. Hematologic (minimal values):

- Absolute neutrophil count > 1,500/mm3

- Hemoglobin > 8.0 g/dl

- Platelet count > 100,000/mm3

5. Hepatic function

- Total bilirubin < Upper limit of normal (ULN)(except for Gilbert's disease)

- AST (SGOT) < 1.5 x ULN

- ALT (SGPT) < 1.5 x ULN

6. Creatinine < 1.5 x ULN

7. Men of childbearing potential must be willing to consent to using effective
contraception while on treatment and for at least 3 months thereafter.

Exclusion Criteria:

1. Patients with a history of seizure, underlying brain injury with loss of
consciousness, transient ischemic attack within the past 12 months, cerebral vascular
accident, brain metastases, brain arteriovenous malformation or the use of concomitant
medications that may lower the seizure threshold

2. History of urological surgery or procedures predisposing to GU complications after
radiation (will be determined by radiation oncologist)

3. History of diverticulitis, rectal bleeding or other lower GI diseases predisposing to
GI complications after radiation (will be determined by radiation oncologist)

4. History of prior chemotherapy or pelvic irradiation,

5. History of prior invasive malignant cancer(s) within the last 5 years except
adequately treated or controlled basal cell or squamous cell carcinoma of the skin.

6. Documented distant metastatic disease. NOTE: pelvic lymphadenopathy is NOT excluded.

7. Prior radical prostatectomy or cryosurgery for prostate cancer or bilateral
orchiectomy.

8. No experimental medications within 30 days of study entry

9. Patients currently taking the following medications:

- CYP2C8 inhibitors (e.g. Gemfibrozil)

- CYP2C8 inducers (e.g. rifampin)

- CYP3A4 inhibitors (itraconazole)

- CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin,
rifampin, rifapentine)