This research study is evaluating a drug called enzalutamide in combination with external beam radiation therapy as a possible treatment for prostate cancer. Presently, when participants receive hormonal therapy with radiation therapy for prostate cancer, medications are given to reduce testosterone levels in the blood stream. This leads to side effects such as loss of sex drive, erectile dysfunction (ED) and decrease in muscle strength. The purpose of this study is test another form of hormonal therapy with radiationtherapy. The medication called enzalutamide will be used with radiation therapy. Instead of lowering testosterone, enzalutamide blocks testosterone in cells. This study will test if enzalutamide when used with radiation will lower the PSA without causing the side effects associated with medications that lower testosterone in the blood stream

The participant will be given a study drug-dosing diary for each of 6 treatment cycles. Each treatment cycle lasts 28 days (4 weeks), during which time the participant will be taking the study drug enzalutamide by mouth (4 pills daily). The diary will also include special instructions for taking the enzalutamide.

The participant will also be undergoing external beam radiation therapy during the study, for a duration of 5,5 weeks. Treatment will be administered on an outpatient basis. This part of the study is considered standard of care.

The participant will be required to have IGRT either by ConeBeam CT study and/or fiducial markers placed within the prostate as part of this study. These are very small gold markers that are placed in the prostate. This procedure is similar to the biopsy that the participant had to diagnose their cancer. These both procedures are routinely performed to permit imaging and position corrections to improve the precision of the external beam (radiation) delivery (Image Guided Radiation Therapy). This is also considered standard of care and is not experimental.

Planned Follow-up: Participants will be followed on study at a 3 month follow-up after treatment (cessation of enzalutamide). Additional follow-up to assess the status of the participant's cancer will be conducted at the discretion of the treating physicians as part of the participant's routine medical care.

Inclusion Criteria:

• Life expectancy of greater than 1 year.

• Diagnosis of histologically confirmed prostate carcinoma

• ECOG Score ≤ 1

• Participants must have an adequate organic function, defined as:

  1. Leukocytes ≥3,000/mcL
  2. Platelets ≥80,000/mcL
  3. Total bilirubin < 2X institutional upper limit
  4. AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
  5. Creatinine < 2x institutional limits .

• Potentially fertile patients should use effective contraceptive methods (barrier methods plus other contraceptive methods) before entering the study and during their participation in the study

• Ability to understand and the willingness to sign a written informed consent

• Patients should be available for clinical follow-up.

• To be able to swallow the medication of the study and to fulfill the requirements of the same one

Exclusion Criteria:

• Received an investigational agent within 4 weeks prior to enrollment

• Stage T4 prostate cancer by clinical examination or radiologic evaluation.

• Hypogonadism or severe androgen deficiency as defined by screening serum testosterone less than 50 ng/dL below the normal range for the institution.

• Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer.

• Receiving concurrent androgens, anti-androgens, estrogens, or progestational agents, or received any of these agents within the 6 months prior to enrollment or having taken finasteride or dutasteride within 30 days of registration.

• History of another active malignancy within the previous 5 years other than curatively treated nonmelanomatous skin cancer and superficial bladder cancer. Participants treated for malignancy with no relapse within two years are eligible to participate in the study.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment.

• History of seizure or any condition or concurrent medication that may predispose to seizure.

• History of loss of consciousness or transient ischemic attack within 12 months prior to enrollment.

• Clinically significant cardiovascular disease, including:

  1. Myocardial infarction within 6 months of enrollment
  2. Uncontrolled angina within 3 months of enrollment
  3. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction ≥ 45%;
  4. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);
  5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
  6. Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit;
  7. Bradycardia as indicated by a heart rate < 50 beats per minute at the Screening visit;
  8. Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the screening visit;
  9. EKG demonstrating equal to or greater than grade III toxicity according the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

• History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of oral study drug(s) within 3 months of enrollment.

• Major surgery within 4 weeks of registration.

• Previous 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 targets the androgen receptor (e.g., enzalutamide, BMS 641988); ketoconazole.

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

• Use of herbal or alternative remedies that may affect hormonal status such as Prostasol or PC-SPES.