Trial Review

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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
17/06/2022
Date data sharing statement initially provided
5/04/2019
Date results provided
5/04/2019
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
Sex
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
31/03/2014
Actual
31/03/2014
Date of last participant enrolment
Anticipated
31/03/2017
Actual
24/03/2017
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
1100
Accrual to date
Final
1125
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 hospital [38] 22582 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
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 postcode(s) [7] 37836 0
3550 - Bendigo
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
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
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
Trial website
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
ENZAMET Trial Coordinator
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
ENZAMET Trial Coordinator
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.study@sydney.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 Supporting Document Provided


Results publications and other study-related documents

Documents added manually
Documents were uploaded by study researchers but have since been removed.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTestosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.2023https://dx.doi.org/10.1016/S1470-2045%2823%2900063-3
Dimensions AIExosome-Based Smart Drug Delivery Tool for Cancer Theranostics2023https://doi.org/10.1021/acsbiomaterials.2c01329
N.B. These documents automatically identified may not have been verified by the study sponsor.