Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer

Men with localised prostate cancer at high risk for recurrence deemed suitable for externalbeam radiation therapy. Inclusion Criteria:

1. Pathological diagnosis of adenocarcinoma of the prostate, judged to be at high riskfor recurrence based on any of the following (in accordance with the InternationalSociety of Urological Pathology (ISUP) Consensus 2005: Gleason score 8-10 OR Gleason score of 4+3 AND clinical T2b-4 AND PSA >20ng/mL OR N1disease (involvement of lymph nodes at or below the bifurcation of the common iliacarteries) defined radiologically as greater than 10mm on short axis using standard CTor MRI, or biopsy proven
2. Age ≥18 years
3. Adequate bone marrow function Haemoglobin (Hb) ≥100g/L and White Cell Count (WCC) ≥ 4.0 x 109/L and platelets ≥100 x 109/L
4. Adequate liver function: Alanine transaminase (ALT) < 2 x ULN and bilirubin < 1.5 xUpper Limit of Normal (ULN), (or if bilirubin is between 1.5 - 2 x ULN, they must havea normal conjugated bilirubin).
5. Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockcroft-Gault)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
7. Study treatment both planned and able to start within 7 days of randomisation.
8. Willing and able to comply with all study requirements, including treatment, andattending required assessments
9. Has completed the baseline HRQOL questionnaires UNLESS is unable to complete becauseof literacy or limited vision
10. Signed, written, informed consent

Exclusion Criteria:

1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine smallcell components
2. Involvement of lymph nodes superior to the common iliac bifurcation, and/or outsidethe pelvis (distant lymph nodes). Lymph node involvement is defined byhistopathological confirmation, or by a short axis measurement >10mm on standardimaging (CT or MRI, but not PET).
3. Any contraindication to external beam radiotherapy
4. History of

• seizure or any condition that may predispose to seizure (e.g., prior corticalstroke or significant brain trauma).
• loss of consciousness or transient ischemic attack within 12 months ofrandomization
• significant cardiovascular disease within the last 3 months: including myocardialinfarction, unstable angina, congestive heart failure (NYHA grade II or greater),ongoing arrhythmias of Grade > 2 , thromboembolic events (e.g., deep veinthrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stableanticoagulant therapy is allowed.

5. Evidence of metastatic disease: minimum imaging required Computed tomography scan (CT) / Magnetic Resonance Imaging (MRI) of the abdomen and pelvis, and Whole Body Bone Scan (WBBS). If equivocal bone scan, follow-up plain films are required to show NO evidenceof cancer if not covered by CT/MRI
6. PSA > 100 ng/mL
7. History of another malignancy within 5 years prior to randomisation except fornon-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasiveurothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours).
8. Concurrent illness, including severe infection that might jeopardize the ability ofthe patient to undergo the procedures outlined in this protocol with reasonable safety

• Human Immunodeficiency Virus (HIV)-infection is not an exclusion criterion if itis controlled with anti-retroviral drugs that are unaffected by concomitantenzalutamide.

9. Presence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule,including alcohol dependence or drug abuse;
10. Patients who are sexually active and not willing/able to use medically acceptableforms of barrier contraception.
11. Use of hormonal therapy or androgen deprivation therapy, including enzalutamide,except in the following setting:

• Use of LHRHA (with or without anti-androgens) for less than 30 days prior torandomisation in the trial.

12. Bilateral orchidectomy or radical prostatectomy
13. Prior brachytherapy or other radiotherapy that would result in an overlap ofradiotherapy fields
14. Participation in other clinical trials of investigational agents for the treatment ofprostate cancer or other diseases.
15. Major surgery within 21 days prior to randomisation
16. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oralabsorption or tolerance of enzalutamide, including difficulty swallowing tablets