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

Randomised Phase 3 Trial of Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer: ENZARAD

The purpose of this study is to determine the effectiveness of enzalutamide as part of adjuvant androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA) in men having radiation therapy for localised prostate cancer at high risk of recurrence.

Men with localised prostate cancer at high risk for recurrence deemed suitable for external beam radiation therapy.

Inclusion Criteria:

1. Pathological diagnosis of adenocarcinoma of the prostate, judged to be at high risk for recurrence based on any of the following (in accordance with the International Society 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 N1 disease (involvement of lymph nodes at or below the bifurcation of the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or 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 x Upper Limit of Normal (ULN), (or if bilirubin is between 1.5 - 2 x ULN, they must have a 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, and attending required assessments

9. Has completed the baseline HRQOL questionnaires UNLESS is unable to complete because of literacy or limited vision

10. Signed, written, informed consent

Exclusion Criteria:

1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components

2. Involvement of lymph nodes superior to the common iliac bifurcation, and/or outside the pelvis (distant lymph nodes). Lymph node involvement is defined by histopathological confirmation, or by a short axis measurement >10mm on standard imaging (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 cortical stroke or significant brain trauma).
   • loss of consciousness or transient ischemic attack within 12 months of randomization
   • significant cardiovascular disease within the last 3 months: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater), ongoing arrhythmias of Grade > 2 , thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant 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 evidence of cancer if not covered by CT/MRI

6. PSA > 100 ng/mL

7. History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours).

8. Concurrent illness, including severe infection that might jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety

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

9. Presence of any psychological, familial, sociological or geographical condition potentially 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 acceptable forms 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 to randomisation in the trial.

12. Bilateral orchidectomy or radical prostatectomy

13. Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields

14. Participation in other clinical trials of investigational agents for the treatment of prostate 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 oral absorption or tolerance of enzalutamide, including difficulty swallowing tablets