ANZCTR - Registration

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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]

ANZUP 1304

Universal Trial Number (UTN)

Trial acronym

ENZAMET

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Prostate Cancer

Condition category

Condition code

Cancer

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]

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]

Overall Survival (Death from any cause)

Timepoint [1]

follow up until 470 deaths are observed

Secondary outcome [1]

To determine the effects on prostate specific antigen progression free survival

Timepoint [1]

within the follow up period and until approximately 470 deaths are observed

Secondary outcome [2]

Clinical progression free survival

Timepoint [2]

within the follow up period and until approximately 470 deaths are observed

Secondary outcome [3]

Adverse events (CTCAE v4.03)

Timepoint [3]

within the follow up period and until approximately 470 deaths are observed

Secondary outcome [4]

Health related quality of life (EORTC QLQ C-30, PR-25 and EQ-5D-5L) monthly or every visit

Timepoint [4]

within the follow up period and until approximately 470 deaths are observed

Secondary outcome [5]

Health outcomes relative to cost (incremental cost effective ratio)

Timepoint [5]

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]

Northern Cancer Institute - Frenchs Forest - Frenchs Forest

Recruitment hospital [2]

Prince of Wales Hospital - Randwick

Recruitment hospital [3]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [4]

Wollongong Hospital - Wollongong

Recruitment hospital [5]

St George Hospital - Kogarah

Recruitment hospital [6]

Sydney Adventist Hospital - Wahroonga

Recruitment hospital [7]

Nepean Hospital - Kingswood

Recruitment hospital [8]

Port Macquarie Base Hospital - Port Macquarie

Recruitment hospital [9]

Peter MacCallum Cancer Institute - East Melbourne

Recruitment hospital [10]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [11]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [12]

Peninsula Oncology Centre - Frankston

Recruitment hospital [13]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [14]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [15]

Nambour General Hospital - Nambour

Recruitment hospital [16]

Gold Coast Hospital - Southport

Recruitment hospital [17]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [18]

Flinders Medical Centre - Bedford Park

Recruitment hospital [19]

Royal Hobart Hospital - Hobart

Recruitment hospital [20]

Royal Darwin Hospital - Tiwi

Recruitment hospital [21]

Concord Repatriation Hospital - Concord

Recruitment hospital [22]

The Chris O’Brien Lifehouse - Camperdown

Recruitment hospital [23]

Tamworth Rural Referral Hospital - Tamworth

Recruitment hospital [24]

The Tweed Hospital - Tweed Heads

Recruitment hospital [25]

Orange Health Service - Orange

Recruitment hospital [26]

Riverina Cancer Care Centre - Wagga Wagga

Recruitment hospital [27]

Box Hill Hospital - Box Hill

Recruitment hospital [28]

Goulburn Valley Health - Shepparton campus - Shepparton

Recruitment hospital [29]

Monash Medical Centre - Moorabbin campus - East Bentleigh

Recruitment hospital [30]

The Townsville Hospital - Douglas

Recruitment hospital [31]

Coffs Harbour Base Hospital - Coffs Harbour

Recruitment hospital [32]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [33]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [34]

Australian Urology Associates - Malvern

Recruitment hospital [35]

Ashford Cancer Centre: Adelaide Cancer Centre - Kurralta Park

Recruitment hospital [36]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [37]

Border Medical Oncology - Albury

Recruitment hospital [38]

Bendigo Health Care Group - Bendigo Hospital - Bendigo

Recruitment postcode(s) [1]

6009 - Nedlands

Recruitment postcode(s) [2]

6150 - Murdoch

Recruitment postcode(s) [3]

3144 - Malvern

Recruitment postcode(s) [4]

5037 - Kurralta Park

Recruitment postcode(s) [5]

3220 - Geelong

Recruitment postcode(s) [6]

3690 - Wodonga

Recruitment postcode(s) [7]

3550 - Bendigo

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Christchurch

Country [2]

Ireland

State/province [2]

Country [3]

United Kingdom

State/province [3]

Country [4]

United States of America

State/province [4]

Country [5]

Canada

State/province [5]

Country [6]

New Zealand

State/province [6]

Waikato

Country [7]

New Zealand

State/province [7]

Auckland

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Astellas Pharma Australia

Address [1]

Lvl4/ 6 Eden Park Drv
Macquarie Park NSW 2113

Country [1]

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]

Other Collaborative groups

Name [1]

ANZUP Cancer Trials Group (Lead Collaborative Group)

Address [1]

Lifehouse, Level 6, 119-143 Missenden Road, Camperdown NSW 2050

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Prince Alfred Hospital Ethics committee

Ethics committee address [1]

Suite 210A 
RPA Medical Centre 
Cnr Missenden Road and Carillon Avenue 
NEWTOWN NSW 2042

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/11/2013

Approval date [1]

30/01/2014

Ethics approval number [1]

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

Prof Ian Davis

Address

Medicine, Sydney Medical School
NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[email protected]

Contact person for public queries

Name

ENZAMET Trial Coordinator

Address

NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[email protected]

Contact person for scientific queries

Name

ENZAMET Trial Coordinator

Address

NHMRC Clinical Trials Centre
The Lifehouse Building, Level 6,
119-143 Missenden Road
Camperdown, NSW, 2050

Country

Australia

Phone

+61 2 9562 5000

Fax

Email

[email protected]

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

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Plain language summary	No		Men with newly diagnosed metastatic prostate cance... [More Details]
Study results article	Yes		Prof Christopher J Sweeney, MBBS; Prof Andrew J Ma... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Testosterone 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.	2023	https://dx.doi.org/10.1016/S1470-2045%2823%2900063-3
Dimensions AI	Exosome-Based Smart Drug Delivery Tool for Cancer Theranostics	2023	https://doi.org/10.1021/acsbiomaterials.2c01329

N.B. These documents automatically identified may not have been verified by the study sponsor.