Clinical trial NCT02446405: Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer
Official title: Randomised Phase 3 Trial of Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer: ENZAMET
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostatic Neoplasms
Keywords: metastatic prostate cancer
prostate cancer
prostate cancer treatment
enzalutamide
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Cancer Trials Ireland
name: Canadian Cancer Trials Group
name: Astellas Pharma Inc
First posted: 2015-05-18
Enrollment: 1125
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:

1. 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.
2. Study site
3. Concomitant "anti-resorptive" therapy to delay skeletal related events when commencing ADT
4. Co-morbidities according to the Adult Co-morbidity Evaluation (ACE-27: 0-1 vs 2-3)
5. Early use of docetaxel defined as use of docetaxel in conjunction with initiation of ADT.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Men starting first line androgen deprivation therapy for metastatic prostate cancer.

Inclusion criteria:

1. Male aged 18 or older with metastatic adenocarcinoma of the prostate
2. Target or non-target lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1
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 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
5. Adequate renal function: calculated creatinine clearance \> 30 ml/min (Cockcroft-Gault)
6. 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.
7. Study treatment both planned and able to start within 7 days after randomisation.
8. Willing and able to comply with all study requirements, including treatment and required assessments
9. Has completed baseline Health-Related Quality of Life (HRQL) questionnaires UNLESS is unable to complete because of limited literacy or vision
10. Signed, written, informed consent

Exclusion Criteria:

1. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components
2. 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.
3. Life expectancy of less than 12 months.
4. 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).
5. 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.
6. 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;
7. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.
8. 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.
9. Prior cytotoxic chemotherapy for prostate cancer, but up to 2 cycles of docetaxel chemotherapy for metastatic disease is permitted.
10. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.

Primary outcomes:
measure: Overall Survival Time
timeFrame: 3 years
Secondary outcomes:
measure: Prostate specific antigen progression free survival time
timeFrame: 3 years
measure: Clinical progression free survival time
timeFrame: 3 years
measure: Adverse events
timeFrame: 3 years
measure: 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))
timeFrame: 3 years
measure: Healthcare resource cost-effectiveness (incremental cost effectiveness ratio)
timeFrame: 3 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Coffs Harbour
country: Australia
facility: Coffs Harbour Health Campus
state: New South Wales
city: Concord
country: Australia
facility: Concord Cancer Centre - Concord Repatriation General Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Cancer Care Centre
state: New South Wales
city: Kogarah
country: Australia
facility: St. George Hospital
state: New South Wales
city: Orange
country: Australia
facility: Central West Cancer Services
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie Base Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Genesis Care North Shore
state: New South Wales
city: Tamworth
country: Australia
facility: Tamworth Rural Referral Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: The Tweed Hospital
state: New South Wales
city: Wagga Wagga
country: Australia
facility: Riverina Cancer Care Centre
state: New South Wales
city: Wahroonga
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Douglas
country: Australia
facility: Townsville Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
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: Adelaide Cancer Centre - Ashford Cancer Care Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Bentleigh East
country: Australia
facility: Monash Cancer Centre Moorabbin
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre - East Melbourne
state: Victoria
city: Fitzroy
country: Australia
facility: St. Vincents Hospital Melbourne
state: Victoria
city: Frankston
country: Australia
facility: Peninsula South Eastern Haematology & Oncology Group- Peninsula Oncology Centre
state: Victoria
city: Geelong
country: Australia
facility: University Hospital Geelong
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Malvern
country: Australia
facility: Australian Urology Associates
state: Victoria
city: Melbourne
country: Australia
facility: Eastern Health Box Hill Hospital
state: Victoria
city: Shepparton
country: Australia
facility: Goulburn Valley Health
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital (formerly Royal Perth Hospital)
state: Western Australia
city: Calgary
country: Canada
facility: Prostate Cancer Institute - Southern Alberta Institute of Urology
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Center
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA Vancouver Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Fredericton
country: Canada
facility: Horizon Health Network - Dr Everett Chalmers Hospital
state: New Brunswick
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: QEII Health Sciences Centre, Capital District Health Authority
state: Nova Scotia
city: Cambridge
country: Canada
facility: Cambridge Memorial Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Cancer Centre
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program Sault Area Hospital
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hôpital Notre-Dame
state: Quebec
city: Québec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Beaumont
country: Ireland
facility: Beaumont Hospital
state: Dublin
city: Dublin
country: Ireland
facility: Beacon Private Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Dublin
country: Ireland
facility: Mater Misercordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Dublin
country: Ireland
facility: St James Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Tallaght
country: Ireland
facility: Adelaide and Meath Hospital - National Children's Hospital
city: Waterford
country: Ireland
facility: University Hospital Waterford
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: Brighton
country: United Kingdom
facility: Royal Sussex Hospital
state: East Sussex
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: Kent
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
state: Wales
city: London
country: United Kingdom
facility: University College Hospital London
city: London
country: United Kingdom
facility: Guys and St Thomas Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Swindon
country: United Kingdom
facility: Great Western Hospital
Study officials:
affiliation: Dana Farber Cancer Institute and ANZUP
name: Christopher Sweeney
role: STUDY_CHAIR
affiliation: ANZUP and Eastern Health Box Hill Hospital
name: Ian Davis
role: STUDY_CHAIR
References:
citation: Stockler MR, Martin AJ, Davis ID, Dhillon HM, Begbie SD, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx GM, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar WR, Pook DW, Reaume MN, Sandhu S, Tan A, Tan TH, Thomson A, Vera-Badillo F, Williams SG, Winter DG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Health-Related Quality of Life in Metastatic, Hormone-Sensitive Prostate Cancer: ENZAMET (ANZUP 1304), an International, Randomized Phase III Trial Led by ANZUP. J Clin Oncol. 2022 Mar 10;40(8):837-846. doi: 10.1200/JCO.21.00941. Epub 2021 Dec 20.
citation: Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, Coskinas X, Frydenberg M, Hague WE, Horvath LG, Joshua AM, Lawrence NJ, Marx G, McCaffrey J, McDermott R, McJannett M, North SA, Parnis F, Parulekar W, Pook DW, Reaume MN, Sandhu SK, Tan A, Tan TH, Thomson A, Tu E, Vera-Badillo F, Williams SG, Yip S, Zhang AY, Zielinski RR, Sweeney CJ; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019 Jul 11;381(2):121-131. doi: 10.1056/NEJMoa1903835. Epub 2019 Jun 2.
citation: Davis ID. Answering Questions and Questioning Answers: More Evidence To Guide Decision-making About Chemohormonal Therapy in Metastatic Prostate Cancer. Eur Urol. 2018 Jun;73(6):856-858. doi: 10.1016/j.eururo.2018.02.020. Epub 2018 Mar 7. No abstract available.