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Trial registered on ANZCTR


Registration number
ACTRN12614000126617
Ethics application status
Approved
Date submitted
13/01/2014
Date registered
3/02/2014
Date last updated
5/06/2019
Date data sharing statement initially provided
5/06/2019
Date results information initially provided
5/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised phase 3 trial of enzalutamide in androgen deprivation therapy with radiation therapy for high risk, clinically localised, prostate cancer
Scientific title
A randomised study of male participants with localised prostate cancer at high risk for recurrence deemed suitable for external beam radiation therapy with a luteinising releasing hormone releasing hormone analogue (LHRHA) treatment combined with the commencement of either 160mg daily Enzalutamide or conventional Non-steroidal anti-androgen (NSAA) to determine the effects of overall survival
Secondary ID [1] 288341 0
ANZUP 1303
Universal Trial Number (UTN)
Trial acronym
ENZARAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 290884 0
Condition category
Condition code
Cancer 291239 291239 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Enzalutamide 160mg daily, by mouth, until disease progression or prohibitive toxicity, adherence monitored by drug tablet return.
Intervention code [1] 288571 0
Treatment: Drugs
Comparator / control treatment
Conventional NSAA (Bicalutamide, nilutamide or flutamide), by mouth, until disease progression or prohibitive toxicity, adherence monitored by drug tablet return.
Control group
Active

Outcomes
Primary outcome [1] 291237 0
Overall Survival (Death from any cause)
Timepoint [1] 291237 0
follow-up until 200 deaths are observed
Secondary outcome [1] 306304 0
Cause-specific survival (prostate cancer, and other causes)
Timepoint [1] 306304 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [2] 306305 0
PSA progression free survival (Phoenix criteria)
Timepoint [2] 306305 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [3] 306308 0
Clinical progression free survival
Timepoint [3] 306308 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [4] 306309 0
Time to subsequent hormonal therapy (restarting ADT)
Timepoint [4] 306309 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [5] 306314 0
Adverse events (CTCAE v4.03)
Timepoint [5] 306314 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [6] 306315 0
Health related quality of life (EORTC QLQC-30,PR-25 & EQ-5D-5L) monthly or every visit
Timepoint [6] 306315 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [7] 306316 0
Health outcomes relative to costs (incremental cost effectiveness ratio)
Timepoint [7] 306316 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [8] 319984 0
Time to castration resistant disease (PCWG2 criteria)
Timepoint [8] 319984 0
within follow up period and until approximately 200 deaths are observed
Secondary outcome [9] 319985 0
Metastasis-free survival
Timepoint [9] 319985 0
within follow up period and until approximately 200 deaths are observed

Eligibility
Key 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 ISUP Consensus 2005: a) Gleason score 8-10 OR b) Gleason score of 4+3 AND clinical T2b-4 AND PSA >20nj/mL OR c) 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 yrs
3) Adequate bone marrow function
4) Adequate liver function
5) Adequate renal function
6) 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
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key 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 a) seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma). b) loss of consciousness or transient ischemic attack within 12 months of randomization c) 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 (NCI CTCAE, version 4.03) , 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 CT / MRI and 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 a) 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: a) 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants must meet all the eligibility criteria. Randomisation will be carried out by site staff via an internet based central randomisation system
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A trial comprising 800 participants that are followed until approximately 200 deaths are observed (e.g. over a 2 year recruitment with an additional follow-up of 5.5 years) provides at least 80% power to detect a 33% reduction in the hazard of death with a 2-sided type 1 error of 0.05 assuming a 5-year survival rate of 76% amongst controls.

The primary analysis will be a comparison of overall survival (OS) in the two treatment arms using a log-rank test. Kaplan-Meier curves for OS will also be prepared. An estimate of the hazard ratio will be obtained using Cox proportional hazards regression. The sensitivity of treatment effect estimates to adjustment for baseline covariates will be explored. Other time-to-event endpoints will be analysed in a comparable fashion to the primary endpoint. The QoL scores collected longitudinally will be analysed using appropriate linear models for repeated measures data.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 1949 0
Westmead Hospital - Westmead
Recruitment hospital [2] 1952 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 1953 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [4] 1954 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 1955 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 1956 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 1957 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 1958 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [9] 1959 0
Nambour General Hospital - Nambour
Recruitment hospital [10] 1960 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [11] 1961 0
Repatriation Hospital - Daw Park
Recruitment hospital [12] 1964 0
Royal Hobart Hospital - Hobart
Recruitment hospital [13] 2542 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [14] 2543 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [15] 2544 0
Liverpool Hospital - Liverpool
Recruitment hospital [16] 2547 0
Epworth Freemasons - Melbourne
Recruitment hospital [17] 2905 0
Gosford Hospital - Gosford
Recruitment hospital [18] 2906 0
Tamworth Rural Referral Hospital - Tamworth
Recruitment hospital [19] 5070 0
Epworth Richmond - Richmond
Recruitment hospital [20] 5071 0
Orange Health Service - Orange
Recruitment hospital [21] 5072 0
Campbelltown Hospital - Campbelltown
Recruitment hospital [22] 5073 0
St Andrew's Toowoomba Hospital - Toowoomba
Recruitment hospital [23] 5074 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [24] 5075 0
The Townsville Hospital - Douglas
Recruitment hospital [25] 5077 0
Prince of Wales Hospital - Randwick
Recruitment hospital [26] 5078 0
Genesis Cancer Care QLD - Tugun
Recruitment hospital [27] 5079 0
Genesis Cancer Care QLD - Southport
Recruitment hospital [28] 5081 0
Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park
Recruitment hospital [29] 5082 0
Ringwood Radiation Oncology Centre - Ringwood East
Recruitment hospital [30] 5083 0
Frankston Radiation Oncology Centre - Frankston
Recruitment hospital [31] 5084 0
Western Radiation Oncology Centre - Footscray
Recruitment hospital [32] 5085 0
Epping Radiation Oncology Centre - Epping
Recruitment hospital [33] 5086 0
Sunshine Hospital - St Albans
Recruitment hospital [34] 5087 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [35] 6790 0
Genesis Cancer Care - Wesley - Auchenflower
Recruitment hospital [36] 6791 0
Genesis Cancer Care - Chermside - Chermside
Recruitment hospital [37] 7896 0
St George Hospital - Kogarah
Recruitment hospital [38] 9600 0
Blacktown Hospital - Blacktown
Recruitment hospital [39] 9601 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [40] 9602 0
Wollongong Hospital - Wollongong
Recruitment hospital [41] 9603 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [42] 9604 0
Peter Maccallum Cancer Centre - Moorabbin Campus - Bentleigh East
Recruitment hospital [43] 9605 0
Genesis Cancer Care - Gateshead
Recruitment hospital [44] 13943 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [45] 13944 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 14446 0
4066 - Auchenflower
Recruitment postcode(s) [2] 14447 0
4032 - Chermside
Recruitment postcode(s) [3] 15852 0
2217 - Kogarah
Recruitment postcode(s) [4] 18356 0
2148 - Blacktown
Recruitment postcode(s) [5] 18357 0
5000 - Adelaide
Recruitment postcode(s) [6] 18358 0
2500 - Wollongong
Recruitment postcode(s) [7] 18359 0
2010 - Darlinghurst
Recruitment postcode(s) [8] 18360 0
3165 - Bentleigh East
Recruitment postcode(s) [9] 18361 0
2290 - Gateshead
Recruitment postcode(s) [10] 26711 0
3550 - Bendigo
Recruitment postcode(s) [11] 26712 0
4215 - Southport
Recruitment outside Australia
Country [1] 7530 0
New Zealand
State/province [1] 7530 0
Christchurch, Auckland, Palmerston North
Country [2] 7531 0
United Kingdom
State/province [2] 7531 0
Country [3] 7532 0
Ireland
State/province [3] 7532 0
Country [4] 7533 0
United States of America
State/province [4] 7533 0
Country [5] 21577 0
Spain
State/province [5] 21577 0
Country [6] 21578 0
Belgium
State/province [6] 21578 0
Country [7] 21579 0
Austria
State/province [7] 21579 0
Country [8] 21580 0
Slovenia
State/province [8] 21580 0

Funding & Sponsors
Funding source category [1] 288536 0
Commercial sector/Industry
Name [1] 288536 0
Astellas Pharma Australia
Address [1] 288536 0
level 4 / 6 eden park drive, Macquarie park NSW 2113
Country [1] 288536 0
Australia
Primary sponsor type
University
Name
NHMRC Clinical Trials Centre (CTC) , University of Sydney
Address
The University of Sydney (USYD),City Rd, Darlington New South Wales 2008
Country
Australia
Secondary sponsor category [1] 288037 0
Other Collaborative groups
Name [1] 288037 0
ANZUP Cancer Trials Group (lead collaborative group)
Address [1] 288037 0
Lifehouse, Level 6, 119-143 Missenden Road, Camperdown NSW 2050
Country [1] 288037 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290404 0
Royal Prince Alfred Hospital Ethics committee
Ethics committee address [1] 290404 0
Suite 210A RPA Medical Centre, Cnr Missenden Road and Carillion Avenue, Newtown, NSW 2042
Ethics committee country [1] 290404 0
Australia
Date submitted for ethics approval [1] 290404 0
03/01/2014
Approval date [1] 290404 0
30/01/2014
Ethics approval number [1] 290404 0
HREC/13/RPAH/559

Summary
Brief summary
The study will compare the effectiveness of standard deprivation therapy and radiation therapy combined either with enzalutamide or with currently available antiandrogen drugs for improving the survival in men with localised prostate cancer at high risk of recurrence. Who is it for? You may be eligible to join this study if you are a male aged 18 years or more who has been diagnosed with adenocarcinoma of the prostate, judged to be at high risk for recurrence. You must also be deemed suitable for external beam radiation therapy. Study details Participants in this study will be randomly (by chance) allocated to one of two treatment groups. Participants in one group will be treated with 160mg Enzalutamide daily by mouth for 24 months. Participants in the other group will receive currently available anti-androgen drugs for 6 months. Anti-androgen drugs block testosterone and related androgens from attaching to molecules in the cancer cell called “androgen receptors.” Blocking this attachment prevents androgens from having their effect. This might provide additional benefit in treating the cancer although this has not yet been proven. Participants will be regularly assessed in order to determine which of these treatments is best at improving the survival of men, as well as the ability of treatments to control prostate cancer, the safety of the treatments, the effects of the treatments on quality of life, and differences in the costs of care.
Trial website
https://www.anzup.org.au/content.aspx?page=trials
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45502 0
A/Prof Scott Williams
Address 45502 0
Monash Cancer Centre/Peter MacCallum Cancer Centre (Moorabbin), Radiation Oncology and Cancer Imaging, 823-865 Centre Road, Bentleigh East, Melbourne, Victoria 3189
Country 45502 0
Australia
Phone 45502 0
+61 3 9905 4301
Fax 45502 0
Email 45502 0
info@anzup.org.au
Contact person for public queries
Name 45503 0
Dr Emily Tu
Address 45503 0
NHMRC Clinical Trials Centre, The Lifehouse Building, Level 6, 119-143 Missenden Road, Camperdown, NSW, 2050
Country 45503 0
Australia
Phone 45503 0
+61 2 9562 5000
Fax 45503 0
Email 45503 0
enzarad@ctc.usyd.edu.au
Contact person for scientific queries
Name 45504 0
Dr Emily Tu
Address 45504 0
NHMRC Clinical Trials Centre, The Lifehouse Building, Level 6, 119-143 Missenden Road, Camperdown, NSW, 2050
Country 45504 0
Australia
Phone 45504 0
+61 2 9562 5000
Fax 45504 0
Email 45504 0
enzarad@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Any information obtained in connection with this research study that can identify a patient will remain confidential. The information collected in this study will be identified by a code number and will only be used for the purpose of this research study.

The study data will be securely and confidentially held electronically by the NHMRC CTC.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary