Clinical trial NCT02446444: Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer
Official title: Randomised Phase 3 Trial of Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer: ENZARAD
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostatic Neoplasms
Keywords: High risk
clinically localised prostate cancer
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: National Health and Medical Research Council, Australia
name: Cancer Trials Ireland
name: Trans Tasman Radiation Oncology Group
name: European Organisation for Research and Treatment of Cancer - EORTC
First posted: 2015-05-18
Enrollment: 802
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Stratification Factors:

* Gleason score (\<=7 versus 8-10),
* Regional lymph nodes involvement (N0 versus N1)
* Clinical T-stage (T2 and below versus T3 and above),
* PSA (\<20ng/mL versus ≥ 20ng/mL)
* Study Site
* Brachytherapy (yes versus no)
* Pelvic Field (yes versus no)
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Metastasis-free survival
timeFrame: 5 years
Secondary outcomes:
measure: Overall survival
timeFrame: 5 years
measure: Prostate cancer-specific survival
timeFrame: 5 years
measure: PSA (Prostate-Specific Antigen) progression-free survival
timeFrame: 5 years
measure: Clinical progression-free survival
timeFrame: 5 years
measure: Time to subsequent hormonal therapy
timeFrame: 5 years
measure: Time to castration-resistant disease (PCWG2 criteria)
timeFrame: 5 years
measure: Safety (adverse events - CTCAE v4.03)
timeFrame: 5 years
measure: Health related quality of life (HRQL)
timeFrame: 5 years
measure: Health outcomes relative to costs (incremental cost effectiveness ratio)
timeFrame: 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Gateshead
country: Australia
facility: Genesis Cancer Care Newcastle
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Orange
country: Australia
facility: Orange Health Service
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Tamworth
country: Australia
facility: Tamworth Rural Referral Hospital
state: New South Wales
city: Wahroonga
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: Genesis Cancer Care Queensland - Wesley and Chermside
state: Queensland
city: Douglas
country: Australia
facility: Townsville Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane & Womens Hospital
state: Queensland
city: Nambour
country: Australia
facility: Nambour General Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Radiation Oncology Services Mater Centre
state: Queensland
city: Southport
country: Australia
facility: ICON - Gold Coast (formerly ROC Gold Coast)
state: Queensland
city: Toowoomba
country: Australia
facility: ICON - Toowoomba (formerly ROC Toowoomba)
state: Queensland
city: Tugun
country: Australia
facility: Genesis Cancer Care Queensland - Tugun and Southport
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital Brisbane
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Kurralta Park
country: Australia
facility: Ashford Cancer Centre Research (Adelaide Cancer Centre)
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Bentleigh East
country: Australia
facility: Peter MacCallum Cancer Centre (Moorabbin Campus)
state: Victoria
city: Box Hill
country: Australia
facility: Eastern Health (Box Hill Hospital)
state: Victoria
city: Epping
country: Australia
facility: Genesis Care - Epping (formerly EROC)
state: Victoria
city: Footscray
country: Australia
facility: Genesis Care - Western (formerly WROC)
state: Victoria
city: Frankston
country: Australia
facility: Genesis Care - Frankston (formerly FROC)
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Richmond
country: Australia
facility: Epworth HealthCare - Richmond
state: Victoria
city: Ringwood East
country: Australia
facility: Genesis Care - Ringwood (formerly RROC)
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Salzburg
country: Austria
facility: Salzburger Landeskliniken - Universitätsklinikum Salzburg
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk- Campus Kennedylaan
city: Cork
country: Ireland
facility: Cork University Hospital
state: Co Cork
city: Galway
country: Ireland
facility: Galway University Hospital
state: Co Galway
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
state: Dublin 7
city: Dublin
country: Ireland
facility: Beacon Private Hospital
city: Dublin
country: Ireland
facility: St Luke's Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Ljubljana
country: Slovenia
facility: The Institute Of Oncology
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
state: Barcelona
city: Donostia
country: Spain
facility: Hospital Donostia
state: Gipuzkoa
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Whitchurch
country: United Kingdom
facility: Velindre Hospital
state: Cardiff
city: Southampton
country: United Kingdom
facility: University Hospital Southhampton
state: Hampshire
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: Kent
city: Chelsea
country: United Kingdom
facility: Royal Marsden Hospital
state: London
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
state: Scotland
city: Bath
country: United Kingdom
facility: Royal United Hospital Bath
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: London
country: United Kingdom
facility: University of London Hospital
city: London
country: United Kingdom
facility: Guys and St Thomas Hospital
city: London
country: United Kingdom
facility: Charring Cross Hospital: Imperial College Healthcare NHS Trust
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital- City Campus
Study officials:
affiliation: ANZUP and Peter MacCallum Cancer Centre
name: Scott Williams
role: STUDY_CHAIR
affiliation: Dana Farber Cancer Institute and ANZUP
name: Paul Nguyen
role: STUDY_CHAIR
References: