EXTEND Exercise Trial

Inclusion Criteria:

1. Male age ≥ 18 years.
2. Histologically-confirmed adenocarcinoma of the prostate.
3. Completion of appropriate prior treatment with local therapy (i.e., prostatectomy, radiation therapy or equivalent), per NCCN Guidelines.
4. Detectable PSA, defined as PSA ≥0.01 ng/ml
5. Appropriate for treatment with ADT in the opinion of the treating physician.
6. Serum total testosterone ≥150 ng/dL (5.2 nmol/L).
7. ECOG performance status of ≤ 1 (Appendix A)
8. Planned treatment with castration therapy (GnRH agonist/antagonist) for ≥8 months.
9. Must not have any of the following absolute contraindications to cardiopulmonary exercise testing and/or aerobic training as determined by the attending oncologist:

   Absolute Contraindications
   * Acute myocardial Infarction (within 3-5 days of any planned study procedures)
   * Unstable angina
   * Uncontrolled arrhythmia causing symptoms or hemodynamic compromise
   * Recurrent syncope
   * Active endocarditis
   * Acute myocarditis or pericarditis
   * Symptomatic severe aortic stenosis
   * Uncontrolled heart failure
   * Acute (within 3 months) pulmonary embolus or pulmonary infarction
   * Thrombosis of lower extremities
   * Suspected dissecting aneurysm
   * Uncontrolled asthma
   * Pulmonary edema
   * Room air desaturation at rest \<85%
   * Respiratory failure
   * Acute non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (i.e. infection, renal failure, thyrotoxicosis)
   * Mental impairment leading to inability to cooperate.
10. Able to swallow enzalutamide and comply with study requirements.
11. Must be able to complete an acceptable cardiopulmonary exercise test (CPET) at baseline (see Section 9), defined as at least one of the following:

    * Achieving a plateau in oxygen consumption concurrent with an increase in power output;
    * Respiratory exchange ratio ≥ 1.1 (RER);
    * Volitional exhaustion with a rating of perceived exertion ≥ 17 (RPE)
12. Must be able to complete an acceptable muscular strength test (assessed using calculated one-repetition maximum (1-RM)) at baseline (see Section 9), in the opinion of the fitness specialist, exercise physiologist, or trained designee administering the test.
13. Life expectancy of ≥ 12 months.
14. Must use a condom if having sex with a pregnant woman.
15. Male subject 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. Two acceptable methods of birth control thus include the following:

    * Condom (barrier method of contraception); AND

    One of the following is required:
    * Established use of oral, or injected or implanted hormonal method of contraception by the female partner;
    * Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner;
    * Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner;
    * Tubal ligation in the female partner;
    * Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy), for more than 6 months
16. Subjects must have normal organ and marrow function as defined below:

    * absolute neutrophil count \>1,500/µL
    * platelets \>100,000/µL
    * total bilirubin \<2.5 X institutional upper limit of normal
    * AST(SGOT)/ALT(SGPT) \<2.5 X institutional upper limit of normal
    * Creatinine ≤ 2.0 OR creatinine clearance \>30 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.

Exclusion Criteria:

1. Definite evidence of metastatic prostate cancer, in the opinion of the treating physician. Pelvic and retroperitoneal lymph nodes \< 2.0 cm in short axis are allowed.
2. Subjects who have had treatments with GnRH agonists/antagonists and/or anti-androgens within 1 year of randomization.
3. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA values (e.g., saw palmetto) or systemic corticosteroids for prostate cancer within 4 weeks of day 29 visit (start of Enzalutamide and ADT).
4. Subjects who have had radiotherapy within 12 weeks prior to entering the study or those who have not recovered from adverse events due to agents or therapies administered for treatment of prostate cancer more than 4 weeks earlier (except urinary, rectal, and sexual side effects related to prostatectomy or radiotherapy are permitted)
5. Subjects who have had any surgical procedure (i.e. TURP, etc.) within 4 weeks prior to entering the study.
6. Subjects who are receiving any other investigational agents.
7. Significant cardiovascular disease, including:

   * Symptomatic left ventricular dysfunction or known baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of \< lower limit of institutional normal (LLN). "Symptomatic" is defined as New York Heart Association (NYHA) Class II or greater. Note: MUGA and ECHCO do NOT need to be measured to establish eligibility for this study.
   * Uncontrolled hypertension (in the opinion of the treating provider).
   * Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug.
   * History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) within 12 months of first dose of study drug.
   * Uncontrolled cardiac arrhythmias.
   * Coronary or peripheral artery bypass graft within 6 months of first dose of study drug.
   * History of CVA, TIA, or rest claudication within 6 months of first dose of study drug.
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements (in the opinion of the treating provider).
9. Subjects with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs the ability to swallow and retain enzalutamide are excluded.
10. History of another invasive cancer within 5 years of randomization with the exceptions of (a) non-melanoma skin cancers and (b) American Joint Committee on Cancer (AJCC) Stage 0 or 1 cancers that have a remote probability of recurrence, in the opinion of the treating physician, in consultation with the principal investigator.
11. Known or suspected brain metastasis or leptomeningeal disease.
12. 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 the Day 1 visit.