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Trial registered on ANZCTR


Registration number
ACTRN12614000110684
Ethics application status
Approved
Date submitted
7/01/2014
Date registered
29/01/2014
Date last updated
2/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised phase 3 trial of enzalutamide in first line androgen deprivation therapy for metastatic prostate cancer: ENZAMET
Scientific title
A randomised study of male participants with metastatic prostate cancer in treatment with a luteinising hormone releasing hormone analogue (LHRHA) or surgical castration combined with the commencement of either 160mg daily Enzalutamide or conventional Non-steroidal anti-androgen (NSAA) to determine the effects of overall survival (an ANZUP Study)
Secondary ID [1] 283862 0
ANZUP 1304
Universal Trial Number (UTN)
Trial acronym
ENZAMET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 290843 0
Condition category
Condition code
Cancer 291207 291207 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 - Enzalutamide 160mg daily by mouth, until disease progression or prohibitive toxicity, adherence monitored by drug tablet return.
Intervention code [1] 288539 0
Treatment: Drugs
Comparator / control treatment
Arm 2 - 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] 291196 0
Overall Survival (Death from any cause)
Timepoint [1] 291196 0
follow up until 470 deaths are observed

Secondary outcome [1] 306215 0
To determine the effects on prostate specific antigen progression free survival
Timepoint [1] 306215 0
within the follow up period and until approximately 470 deaths are observed
Secondary outcome [2] 306216 0
Clinical progression free survival
Timepoint [2] 306216 0
within the follow up period and until approximately 470 deaths are observed
Secondary outcome [3] 306217 0
Adverse events (CTCAE v4.03)
Timepoint [3] 306217 0
within the follow up period and until approximately 470 deaths are observed
Secondary outcome [4] 306218 0
Health related quality of life (EORTC QLQ C-30, PR-25 and EQ-5D-5L) monthly or every visit
Timepoint [4] 306218 0
within the follow up period and until approximately 470 deaths are observed
Secondary outcome [5] 306219 0
Health outcomes relative to cost (incremental cost effective ratio)
Timepoint [5] 306219 0
within the follow up period and until approximately 470 deaths are observed

Eligibility
Key inclusion criteria
1. Male aged 18 or older with metastatic adenocarcinoma of the prostate defined by a) Documented histopathology or cytopathology of prostate adenocarcinoma from a biopsy of a metastatic site OR b) Documented histopathology of prostate adenocarcinoma from a TRUS biopsy, radical prostatectomy, or TURP and metastatic disease consistent with prostate cancer. OR c) Metastatic disease typical of prostate cancer (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA that is rising and >20ng/mL
2. Target or non-target lesions according to RECIST 1.1
3. Adequate bone marrow function: Hb =100g/L and WCC = 4.0 x 109/L and platelets =100 x 109/L.
4. Adequate liver function: ALT < 2 x ULN and bilirubin < 1.5 x ULN, (or if bilirubin is between 1.5-2x ULN, they must have a normal conjugated bilirubin). If liver metastases are present ALT must be < 5xULN
5. Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockroft-Gault,)
6. 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 HRQL questionnaires UNLESS is unable to complete because of limited literacy or 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. 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 functional capacity class II or greater), ongoing arrhythmias of Grade >2 [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. 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:
a. Started less than 12 weeks prior to randomisation AND 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.
b. 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.as per section 5.3.2.4 is allowed.
10. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.

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 1,100 participants that are followed until approximately 470 deaths are observed (e.g. over a 2 year recruitment with an additional follow-up of 3.5 years) provides over 80% power to detect a 25% reduction in the hazard of death with a 2-sided type 1 error of 0.05 assuming a 3-year survival rate of 65% 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 hazard 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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 1906 0
Northern Cancer Institute - Frenchs Forest - Frenchs Forest
Recruitment hospital [2] 1908 0
Prince of Wales Hospital - Randwick
Recruitment hospital [3] 1912 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [4] 1914 0
Wollongong Hospital - Wollongong
Recruitment hospital [5] 1915 0
St George Hospital - Kogarah
Recruitment hospital [6] 1917 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [7] 1918 0
Nepean Hospital - Kingswood
Recruitment hospital [8] 1919 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [9] 1920 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [10] 1921 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [11] 1923 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [12] 1924 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [13] 1925 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [14] 1926 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [15] 1927 0
Nambour General Hospital - Nambour
Recruitment hospital [16] 1928 0
Gold Coast Hospital - Southport
Recruitment hospital [17] 1929 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [18] 1930 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [19] 1933 0
Royal Hobart Hospital - Hobart
Recruitment hospital [20] 1934 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [21] 4456 0
Concord Repatriation Hospital - Concord
Recruitment hospital [22] 4457 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [23] 4458 0
Tamworth Rural Referral Hospital - Tamworth
Recruitment hospital [24] 4459 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [25] 4460 0
Orange Health Service - Orange
Recruitment hospital [26] 4461 0
Riverina Cancer Care Centre - Wagga Wagga
Recruitment hospital [27] 4462 0
Box Hill Hospital - Box Hill
Recruitment hospital [28] 4463 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [29] 4464 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [30] 4465 0
The Townsville Hospital - Douglas
Recruitment hospital [31] 4466 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [32] 7207 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [33] 7208 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [34] 7209 0
Australian Urology Associates - Malvern
Recruitment hospital [35] 7210 0
Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park
Recruitment hospital [36] 7211 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [37] 7212 0
Border Medical Oncology - Albury
Recruitment postcode(s) [1] 14971 0
6009 - Nedlands
Recruitment postcode(s) [2] 14972 0
6150 - Murdoch
Recruitment postcode(s) [3] 14973 0
3144 - Malvern
Recruitment postcode(s) [4] 14974 0
5037 - Kurralta Park
Recruitment postcode(s) [5] 14975 0
3220 - Geelong
Recruitment postcode(s) [6] 14976 0
3690 - Wodonga
Recruitment outside Australia
Country [1] 5719 0
New Zealand
State/province [1] 5719 0
Christchurch
Country [2] 5720 0
Ireland
State/province [2] 5720 0
Country [3] 5721 0
United Kingdom
State/province [3] 5721 0
Country [4] 5722 0
United States of America
State/province [4] 5722 0
Country [5] 5723 0
Canada
State/province [5] 5723 0
Country [6] 7239 0
New Zealand
State/province [6] 7239 0
Waikato
Country [7] 7240 0
New Zealand
State/province [7] 7240 0
Auckland

Funding & Sponsors
Funding source category [1] 288509 0
Commercial sector/Industry
Name [1] 288509 0
Astellas Pharma Australia
Address [1] 288509 0
Lvl4/ 6 Eden Park Drv
Macquarie Park NSW 2113
Country [1] 288509 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] 288242 0
Other Collaborative groups
Name [1] 288242 0
ANZUP Cancer Trials Group (Lead Collaborative Group)
Address [1] 288242 0
Lifehouse, Level 6, 119-143 Missenden Road, Camperdown NSW 2050
Country [1] 288242 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290371 0
Royal Prince Alfred Hospital Ethics committee
Ethics committee address [1] 290371 0
Suite 210A
RPA Medical Centre
Cnr Missenden Road and Carillon Avenue
NEWTOWN NSW 2042
Ethics committee country [1] 290371 0
Australia
Date submitted for ethics approval [1] 290371 0
26/11/2013
Approval date [1] 290371 0
30/01/2014
Ethics approval number [1] 290371 0
HREC/13/RPAH/558

Summary
Brief summary
Participants are invited to take part in this research study to test a new treatment combination for prostate cancer. This is because they have cancer that started in the prostate and has spread to other parts of their body. This is known as metastatic prostate cancer. Current treatment for newly diagnosed metastatic prostate cancer involves androgen deprivation therapy(ADT). Androgen deprivation therapy has two components:

1. The main component is by stopping the release of androgen from the testicles. This is mainly done by using
drugs that prevent the testicles from making androgens, and therefore reducing the levels of androgens in the body to low levels. These drugs are called luteinising hormone releasing hormone analogues (LHRHA). These drugs are given as injections. This is usually part of the standard initial treatment for men in your situation. The other way of reducing androgen production by the testicles is with a surgical operation to remove both testicles. This is not part of the trial. If participants have already had this surgical procedure or it is planned to be done, they will not need to be on LHRHA, but can still take part in this study.

2. The second component of ADT is to block the effects of androgens produced in other parts of the body with antiandrogen drugs. Antiandrogen 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. Several different types of antiandrogen drugs are available for use already. Enzalutamide is a new antiandrogen that is not yet approved for use in Australia. This study will compare the effectiveness of enzalutamide versus the currently available antiandrogen drugs when used on a background of treatment with a LHRHA (or surgical removal of the testicles). The main aim of the study is to see which of these combinations is best at improving the survival of men in this situation. Recent studies show promising results with the use of enzalutamide in participants who had been treated with androgen deprivation therapy and were no longer responding to the standard antiandrogens, this is known as castrate resistant prostate cancer (CRPC), which is a more advanced stage than the type of metastatic prostate cancer being studied here. With this stage of metastatic prostate cancer there is no evidence yet on which treatment is best to treat it. To do this, a total of 1100 participants will participate where half the participants on the study will receive enzalutamide with a LHRHA or surgical operation to remove both testicles and the other half (550 participants) will receive already available antiandrogens (but not enzalutamide) with a LHRHA or surgical operation to remove testicles. All participants on this study will receive active therapy and no placebo treatment will be used. The study is open label, meaning that both the participants and the investigators will know the treatment the participant will receive.
Trial website
https://www.anzup.org.au/content.aspx?page=trials
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45358 0
Prof Ian Davis
Address 45358 0
Medicine, Sydney Medical School
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 45358 0
Australia
Phone 45358 0
+61 2 9562 5000
Fax 45358 0
Email 45358 0
info@anzup.org.au
Contact person for public queries
Name 45359 0
Dr Emily Tu
Address 45359 0
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 45359 0
Australia
Phone 45359 0
+61 2 9562 5000
Fax 45359 0
Email 45359 0
enzamet@ctc.usyd.edu.au
Contact person for scientific queries
Name 45360 0
Dr Emily Tu
Address 45360 0
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050
Country 45360 0
Australia
Phone 45360 0
+61 2 9562 5000
Fax 45360 0
Email 45360 0
enzamet@ctc.usyd.edu.au

No data has been provided for results reporting
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