Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of enzalutamide, versus a conventional non-steroidal anti androgen (NSAA), when combined with a luteinizing hormone releasing hormone analog (LHRHA) or surgical castration, as first line androgen deprivation therapy (ADT) for newly diagnosed metastatic prostate cancer.

Official Title
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Randomised Phase 3 Trial of Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer: ENZAMET

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: NSAA
* Drug: LHRHA or Surgical Castration


Participation Criteria
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Eligibility Criteria
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Men starting first line androgen deprivation therapy for metastatic prostate cancer. Inclusion criteria: Male aged 18 or older with metastatic adenocarcinoma of the prostate Target or non-target lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Adequate bone marrow function: Haemoglobin (Hb) ≥100g/L and White Cell Count (WCC) ≥ 4.0 x 109/L and platelets ≥100 x 109/L. Adequate liver function: Alanine transaminase (ALT) < 2 x Upper Limit of Normal (ULN) and bilirubin < 1.5 x ULN, (or if bilirubin is between 1.5-2 x ULN, they must have a normal conjugated bilirubin). If liver metastases are present ALT must be < 5 x ULN Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockcroft-Gault) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with performance status 2 are only eligible if the decline in performance status is due to metastatic prostate cancer. Study treatment both planned and able to start within 7 days after randomisation. Willing and able to comply with all study requirements, including treatment and required assessments Has completed baseline Health-Related Quality of Life (HRQL) questionnaires UNLESS is unable to complete because of limited literacy or vision Signed, written, informed consent Exclusion Criteria: Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components 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, ongoing arrhythmias of Grade >2 [National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03], thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. Life expectancy of less than 12 months. History of another malignancy within 5 years prior to randomisation, except for either non- melanomatous carcinoma of the skin or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta and low grade T1 tumours). Concurrent illness, including severe infection that might jeopardize the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety a. Human Immunodeficiency Virus (HIV)-infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant enzalutamide. 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; Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception. Prior ADT for prostate cancer (including bilateral orchidectomy), except in the following settings: Started less than 12 weeks prior to randomisation AND Prostate Specific Antigen (PSA) is stable or falling. The 12 weeks starts from whichever of the following occurs earliest: first dose of oral anti- androgen, LHRHA, or surgical castration. In the adjuvant setting, where the completion of adjuvant hormonal therapy was more than 12 months prior to randomisation AND the total duration of hormonal treatment did not exceed 24 months. For depot preparations, hormonal therapy is deemed to have started with the first dose and to have been completed when the next dose would otherwise have been due, e.g. 12 weeks after the last dose of depot goserelin 10.8mg. Prior cytotoxic chemotherapy for prostate cancer, but up to 2 cycles of docetaxel chemotherapy for metastatic disease is permitted. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Stratification factors: High volume disease (yes versus no), characterised as: 4 or more bone metastases, one of which is outside the vertebral column and pelvis AND/OR Visceral metastases (e.g. lung, pleura, liver, adrenal and others) Lymph node involvement or bladder invasion do NOT qualify as visceral disease. Study site Concomitant anti-resorptive therapy to delay skeletal related events when commencing ADT Co-morbidities according to the Adult Co-morbidity Evaluation (ACE-27: 0-1 vs 2-3) Early use of docetaxel defined as use of docetaxel in conjunction with initiation of ADT.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide<br>Enzalutamide is 160 mg daily, by mouth, until clinical disease progression or prohibitive toxicity. All participants are to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration is at the discretion of the treating clinician. | Drug: Enzalutamide<br> <br> Drug: LHRHA or Surgical Castration<br> <br> |
| Active Comparator: Conventional NSAA<br>Conventional NSAA, by mouth until clinical disease progression or prohibitive toxicity. All participants are to receive standard background therapy with a LHRHA or surgical castration, as per standard of care. The choice of the LHRHA or surgical castration is at the discretion of the treating clinician. | Drug: NSAA<br> <br> Drug: LHRHA or Surgical Castration<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | the interval from the date of randomisation to date of death. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate specific antigen progression free survival time | the interval from the date of randomisation to the date of first evidence of PSA progression, clinical progression, or death from any cause, whichever occurs first, or the date of last known follow-up without PSA progression PSA progression is defined as: a rise in PSA by more than 25% AND more than 2ng/mL | 3 years | 
| Clinical progression free survival time | the interval from the date of randomisation to the date of first clinical evidence of disease progression or death from any cause, whichever occurs first, or the date of last known follow-up without clinical progression | 3 years | 
| Adverse events | The NCI Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.03) will be used to classify and grade the intensity of adverse events during study treatment | 3 years | 
| Health-related quality of life (EORTC Core Quality of Life Questionnaire (QLQ C-30), Quality of Life Questionnaire for Prostate Cancer (PR-25), Euroqol 5 item preference-based measure of health (EQ-5 D-5L)) | HRQL will be reported by participants using the EORTC core quality of life questionnaire (QLQ C-30) and prostate cancer specific module (PR-25). The EQ-5D-5L will be used to derive utility scores suitable for quality adjusted survival analyses | 3 years | 
| Healthcare resource cost-effectiveness (incremental cost effectiveness ratio) | Information on the following areas of health-care resource usage will be collected: hospitalisations, visits to health professionals, and medications Australian unit costs will be applied to the resource usage data to estimate the incremental cost of the addition of enzalutamide to standard treatment | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic prostate cancer, prostate cancer, prostate cancer treatment, enzalutamide