Enzalutamide and Leuprolide Acetate before, during, and after Radiation Therapy in Treating Patients with High-Risk Localized or Locally Advanced Prostate Cancer

Inclusion Criteria

• Histologically proven adenocarcinoma of the prostate obtained within 6 months of screening; patients in whom a diagnosis of high-risk localized or locally-advanced prostatic adenocarcinoma is suspected based on a serum PSA > 20 ng/mL or clinical T3 disease by digital rectal examination, but who have not yet undergone diagnostic prostate biopsy, will be eligible for screening and initial MRI and targeted prostate cancer biopsies which will be obtained at the same time as diagnostic biopsies; those patients in whom the diagnostic biopsies confirm prostatic adenocarcinoma will be permitted to continue with study treatment if they meet all additional eligibility criteria
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcl
• Hemoglobin >= 10 g/dL
• Total bilirubin =< 1.5 X institutional upper limit of normal (except for patients with documented Gilbert’s disease)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum pyruvate glutamate transaminase [SPGT]) =< 2.5 X institutional upper limit of normal
• Creatinine =< 1.5 X institutional upper limit of normal or estimated glomerular filtration rate < 45 mL/min/1.73 m^2
• Serum testosterone >= 100 ng/dL
• Men who are sexually active with female partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant following intercourse with a study participant during his participation in this study, she should inform her treating physician immediately, and the study principal investigator should be informed immediately
• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Patients must be candidates for long-term androgen deprivation in combination with EBRT for the treatment of high-risk or locally-advanced prostate cancer by the following criteria: * High risk disease: T3a or Gleason 8-10 or serum PSA > 20 ng/mL * Gleason 7 also allowed if > 50% of cores positive for cancer or PSA velocity > 2 ng/mL/year in preceding 12 months * Locally advanced (very high risk) disease: T3b-T4
• Patients may have radiographic evidence of metastasis in regional lymph nodes (N1 disease as defined by the National Comprehensive Cancer Network Prostate Cancer Guideline version 3.2012) at the discretion of the treating physicians, if regional lymph nodes can be included in the planned radiation field
• Participants in the study must permit targeted prostate biopsy prior to initiation of study treatment and at the time of fiducial marker placement
• Able and willing to provide written authorization for use and release of health and research study information
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

• Prior treatment with the following agents known to have endocrine effects on prostate cancer: GnRH agonist, GnRH antagonist, anti-androgen (bicalutamide, nilutamide, flutamide), ketoconazole, diethylstilbestrol, estrogen, abiraterone acetate; concurrent use of 5-alpha-reductase inhibitors finasteride or dutasteride is permitted for patients who have been already receiving either of these treatments for at least 1 month at the time of study enrollment; baseline PSA must have been obtained in such patients after at least 1 month on 5-alpha-reductase treatment; initiation of treatment with 5-alpha-reductase inhibitors is not permitted within the first 12 months of study participation
• Concomitant treatment with agents thought to have endocrine effects on prostate cancer: PC-SPES, saw palmetto
• Treatment with corticosteroids within 4 weeks prior to enrollment
• Treatment with androgens within 6 months prior to study enrollment
• Subjects may not be receiving any other investigational agents; concurrent enrollment in another clinical investigational drug or device study is prohibited
• Prostate cancer metastases to the bones, viscera, or non-regional lymph nodes (lymph nodes other than pelvic lymph nodes within the radiation treatment field)
• Serum PSA > 160 ng/dL
• History of malignancy (other than non-melanoma skin cancer) within 5 years of enrollment
• Patients with histologic evidence of small cell carcinoma of the prostate will not be eligible
• Treatment for malignancy with anticancer therapy, including cytotoxic agents, hormonal agents, or immunotherapy, within 5 years of enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or other agents used in this study
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (> New York Heart Association [NYHA] class II heart failure), unstable angina pectoris, cardiac arrhythmia, chronic active hepatitis, acute hepatitis, uncontrolled diabetes mellitus, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with any of the following within 6 months of enrollment: deep vein thrombosis, pulmonary embolus, myocardial infarction, cerebrovascular accident, unexplained loss of consciousness
• Patients with any history of seizure or seizure disorder
• Patients with medical conditions which, in the opinion of the investigators, would pose undue risk to the patient
• Subjects unwilling to use contraceptives if they have sexual intercourse with a female partner of child-bearing potential while receiving treatment on this study
• Standard contraindications to MRI: for example, MRI non-compatible cardiac pacemakers, intracranial clips, foreign metal objects in the body and others as defined in the University of Texas (UT) Southwestern Institutional MRI Safety Policy
• The following medications are prohibited during the study: * Substrates of cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6), cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) with a narrow therapeutic index, including paclitaxel, phenytoin, warfarin, omeprazole * Substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) with a narrow therapeutic index, including alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus * Strong CYP2C8 inhibitors, including gemfibrozil * Strong CYP3A4/5 inhibitors, including clarithromycin, itraconazole, ketoconazole