Management of Castration-Resistant Prostate Cancer with Oligometastases

Inclusion Criteria:

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

2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrinedifferentiation or small cell features;

3. Ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone (GnRH)analogue or bilateral orchiectomy (i.e., surgical or medical castration);

4. Patients who have not had a bilateral orchiectomy must have a plan to maintaineffective GnRH analogue therapy for the duration of the trial;

5. Serum testosterone level ≤ 1.7 nmol/L (50 ng/dL) at the Screening visit;

6. Patients receiving bisphosphonate therapy/Xgeva must have been on stable doses forat least 4 weeks;

7. Progressive disease at study entry defined as one or more of the following threecriteria that occurred while the patient was on androgen deprivation therapy asdefined in eligibility criterion #3:

8. PSA progression defined by a minimum of two rising PSA levels with an intervalof ≥ 1 week between each determination. Patients who received an anti-androgenmust have progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6weeks since last bicalutamide or nilutamide). The PSA value at the Screeningvisit should be ≥ 2 μg/L (2 ng/mL);

9. Metastatic disease documented by bone lesions on bone scan or by measurablesoft tissue disease by CT/MRI. Patients whose disease spread is limited toregional pelvic lymph nodes, and previously radiated, are not eligible; i. Up to 5 metastatic sites ii. ≤ 4 tumours within any given organ system, excludingbrain and liver (e.g. up to 4 bone metastases, or 4 lung metastases) iii. All sitesof disease must be amenable to SBRT with no history of the metastases beingirradiated; iv. In the case of a suspicious lesion in an unusual location such aslung or thoracic lymph nodes (without other abdominal lymph nodes), a biopsy shouldconfirm prostate cancer origin.

10. No prior cytotoxic chemotherapy for prostate cancer;

11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 or Karnofskyperformance status of > 70% or higher;

12. Patients and their female partners of childbearing potential must be willing to usetwo forms of contraception (one of which must include a condom as a barrier methodof contraception during sexual activity) throughout the duration of the studystarting at screening and continuing for 3 months after the last dose of study drugor per local guidelines where these require additional description of birth controlmethods. These contraceptive methods must include the following:

13. The use of condoms (barrier method)AND one of the following:

14. the use of oral, injected or implanted hormonal methods of contraception by afemale partner;

15. placement of an intrauterine device (IUD) or intrauterine system (IUS) by afemale partner;

16. additional barrier method, such as occlusive cap (diaphragm or cervical/vaultcap) with spermicidal foam/gel/film/cream/suppository by a female partner;

17. tube ligation in the female partner;

18. vasectomy or other procedure resulting in infertility (eg. bilateralorchiectomy) for ≥ 6 months. If the patient's partner is a pregnant woman, the patient must use a condom duringsexual activity during and for 3 months after treatment with enzalutamide.

19. Patients must agree to not donate sperm while taking study drug

20. Estimated life expectancy of ≥ 6 months;

21. Ability to swallow the study drug whole and comply with study.

Exclusion Criteria:

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

2. Known or suspected brain metastasis or active leptomeningeal disease;

3. History of another malignancy within the previous 5 years other than curativelytreated non-melanoma skin cancer;

4. Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 5.6 mmol/L (9 g/dL) at the Screening visit (NOTE: patients may not have received anygrowth factors within 7 days or blood transfusions within 28 days of the hematologiclaboratory values obtained at the Screening visit);

5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the Screening visit;

6. Creatinine > 177 μmol/L (2 mg/dL) at the Screening visit;

7. Albumin < 30 g/L (3.0 g/dL) at the Screening visit;

8. History of seizure or any condition that may predispose to seizure (e.g., priorcortical stroke or significant brain trauma). Also, history of loss of consciousnessor transient ischemic attack within 12 months of enrollment (Day 1 visit);

9. Clinically significant cardiovascular disease including:

10. Myocardial infarction within 6 months;

11. Uncontrolled angina within 3 months;

12. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, orpatients with history of congestive heart failure NYHA class 3 or 4 in thepast, unless a screening echocardiogram or multi-gated acquisition scanperformed within three months results in a left ventricular ejection fractionthat is ≥ 45%;

13. History of clinically significant ventricular arrhythmias (e.g., ventriculartachycardia, ventricular fibrillation, torsades de pointes);

14. History of Mobitz II second degree or third degree heart block without apermanent pacemaker in place;

15. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit;

16. Bradycardia as indicated by a heart rate of < 50 beats per minute on theScreening ECG;

17. Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg ordiastolic blood pressure > 105 mmHg at the Screening visit.

18. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active pepticulcer disease within last 3 months);

19. Major surgery within 4 weeks of enrollment (Day 1 Visit);

20. Use of opiate analgesics (eg. morphine, fentanyl, etc.) for pain from prostatecancer within 4 weeks of enrollment (Day 1 visit). This does not apply tonon-morphine drugs like codeine;

21. Radiation therapy for treatment of the primary tumour within 3 weeks of enrollment (Day 1 visit);

22. Radiation or radionuclide therapy for treatment of metastasis;

23. Primary disease not treated

24. More than 5 metastases

25. Hormone naïve prostate cancer patients

26. Treatment with flutamide within 4 weeks of enrollment (Day 1 visit);

27. Treatment with bicalutamide or nilutamide within 6 weeks of enrollment (Day 1visit);

28. Treatment with 5-α reductase inhibitors (finasteride, dutasteride), estrogens,cytproterone within 4 weeks of enrollment (Day 1 visit)

29. Treatment with systemic biologic therapy for prostate cancer (other than approvedbone targeted agents and GnRH-analogue therapy) or other agents with anti-tumouractivity within 4 weeks of enrollment (Day 1 visit);

30. History of prostate cancer progression on ketoconazole;

31. Prior use, or participation in a clinical trial, of an investigational agent thatblocks androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) ortargets the androgen receptor (e.g., BMS 641988);

32. Participation in a previous clinical trial of enzalutamide;

33. Use of an investigational agent within 4 weeks of enrollment (Day 1 visit);

34. Use of herbal products that may have hormonal anti-prostate cancer activity and/orare known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroidsgreater than the equivalent of 10 mg of prednisone per day within four weeks ofenrollment (Day 1 visit);

35. Any condition or reason that, in the opinion of the Investigator, interferes withthe ability of the patient to participate in the trial, which places the patient atundue risk, or complicates the interpretation of safety data.