Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer

Prostatic Neoplasms Clinical Trial

— ENZARAD  

Official title:

Randomised Phase 3 Trial of Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer: ENZARAD

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02446444
• Other study ID #: ANZUP1303
• Secondary ID: ACTRN12614000126
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 2014
• Est. completion date: December 2025

Study information

• Verified date: February 2024
• Source: University of Sydney
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the effectiveness of enzalutamide as part of adjuvant androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA) in men having radiation therapy for localised prostate cancer at high risk of recurrence.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 802
• Est. completion date: December 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Men with localised prostate cancer at high risk for recurrence deemed suitable for external beam radiation therapy.

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 International Society of Urological Pathology (ISUP) Consensus 2005: Gleason score 8-10 OR Gleason score of 4+3 AND clinical T2b-4 AND PSA >20ng/mL OR 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 years

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 ULN and bilirubin < 1.5 x Upper Limit of Normal (ULN), (or if bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin).

5. Adequate renal function: calculated creatinine clearance > 30 ml/min (Cockcroft-Gault)

6. Eastern Cooperative Oncology Group (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

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

• 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 (NYHA grade II or greater), ongoing arrhythmias of Grade > 2 , 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 Computed tomography scan (CT) / Magnetic Resonance Imaging (MRI) of the abdomen and pelvis, and Whole Body Bone Scan (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

• Human Immunodeficiency Virus (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:

• 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

Related Conditions & MeSH terms

• Prostatic Neoplasms

Intervention

Drug:
• Enzalutamide

• Conventional NSAA

• LHRHA

Radiation:
• External Beam Radiotherapy (78 Gy in 39 fractions or 46 Gy in 23 fractions plus brachytherapy boost)

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Genesis Cancer Care Queensland - Wesley and Chermside	Auchenflower	Queensland
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Peter MacCallum Cancer Centre	Bendigo	Victoria
Australia	Peter MacCallum Cancer Centre (Moorabbin Campus)	Bentleigh East	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Eastern Health (Box Hill Hospital)	Box Hill	Victoria
Australia	Campbelltown Hospital	Campbelltown	New South Wales
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Townsville Hospital	Douglas	Queensland
Australia	Genesis Care - Epping (formerly EROC)	Epping	Victoria
Australia	Genesis Care - Western (formerly WROC)	Footscray	Victoria
Australia	Genesis Care - Frankston (formerly FROC)	Frankston	Victoria
Australia	Genesis Cancer Care Newcastle	Gateshead	New South Wales
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Brisbane & Womens Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	St George Hospital	Kogarah	New South Wales
Australia	Ashford Cancer Centre Research (Adelaide Cancer Centre)	Kurralta Park	South Australia
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Nambour General Hospital	Nambour	Queensland
Australia	Orange Health Service	Orange	New South Wales
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Epworth HealthCare - Richmond	Richmond	Victoria
Australia	Genesis Care - Ringwood (formerly RROC)	Ringwood East	Victoria
Australia	Radiation Oncology Services Mater Centre	South Brisbane	Queensland
Australia	ICON - Gold Coast (formerly ROC Gold Coast)	Southport	Queensland
Australia	Sunshine Hospital	St Albans	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	St Vincent's Hospital	Sydney	New South Wales
Australia	Tamworth Rural Referral Hospital	Tamworth	New South Wales
Australia	ICON - Toowoomba (formerly ROC Toowoomba)	Toowoomba	Queensland
Australia	Genesis Cancer Care Queensland - Tugun and Southport	Tugun	Queensland
Australia	Sydney Adventist Hospital	Wahroonga	New South Wales
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital Brisbane	Woolloongabba	Queensland
Austria	Salzburger Landeskliniken - Universitätsklinikum Salzburg	Salzburg
Belgium	AZ Groeninge Kortrijk- Campus Kennedylaan	Kortrijk
Ireland	Cork University Hospital	Cork	Co Cork
Ireland	Beacon Private Hospital	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin	Dublin 7
Ireland	Mater Private Hospital	Dublin
Ireland	St Luke's Hospital	Dublin
Ireland	Galway University Hospital	Galway	Co Galway
New Zealand	Auckland City Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Palmerston North Hospital	Palmerston North
Slovenia	The Institute Of Oncology	Ljubljana
Spain	Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)	Badalona	Barcelona
Spain	Hospital Donostia	Donostia	Gipuzkoa
Spain	Hospital Universitario de Salamanca	Salamanca
United Kingdom	Royal United Hospital Bath	Bath
United Kingdom	Addenbrookes Hospital	Cambridge
United Kingdom	Kent and Canterbury Hospital	Canterbury	Kent
United Kingdom	Royal Marsden Hospital	Chelsea	London
United Kingdom	Western General Hospital	Edinburgh	Scotland
United Kingdom	Charring Cross Hospital: Imperial College Healthcare NHS Trust	London
United Kingdom	Guys and St Thomas Hospital	London
United Kingdom	University of London Hospital	London
United Kingdom	Nottingham City Hospital- City Campus	Nottingham
United Kingdom	University Hospital Southhampton	Southampton	Hampshire
United Kingdom	Velindre Hospital	Whitchurch	Cardiff
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts

Sponsors (6)

Lead Sponsor	Collaborator
University of Sydney	Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Cancer Trials Ireland, European Organisation for Research and Treatment of Cancer - EORTC, National Health and Medical Research Council, Australia, Trans Tasman Radiation Oncology Group

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Ireland,  New Zealand,  Slovenia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Metastasis-free survival	Metastasis free survival (MFS) is defined as the interval from the date of randomisation to the date of first evidence of metastasis or death from any cause, whichever occurs first, or the date of last known follow-up alive and without metastases.; Evidence of metastasis includes findings on whole body bone scan (WBBS) or CT or MRI that are either characteristic of metastatic prostate cancer, and/or confirmed by other test results, e.g. cytology or histopathology, and lesion qualifies as new metastatic disease per RECIST 1.1. Detection of metastasis by other modalities, eg Ga-68 PSMA (Prostate Specific Membrane Antigen) PET, does not constitute an event unless confirmed by WBBS or CT or MR	5 years
Secondary	Overall survival	Overall survival (OS) is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known follow-up alive.	5 years
Secondary	Prostate cancer-specific survival	Prostate cancer-specific survival is defined as the interval from the date of randomisation to the date of death from prostate cancer, or the date of last known follow-up alive.	5 years
Secondary	PSA (Prostate-Specific Antigen) progression-free survival	PSA progression-free survival is defined as the interval from the date of randomisation to the date of first evidence of PSA progression, clinical progression, or death from any cause, whichever occurs first, or the date of last known follow-up without PSA progression and without clinical progression.; PSA progression as defined by the Phoenix criteria: an increase in PSA of more than 2ng/mL above the nadir (lowest) PSA level.	5 years
Secondary	Clinical progression-free survival	Clinical progression-free survival is defined as the interval from the date of randomisation to the date of first clinical evidence of disease progression or death from any cause, whichever occurs first, or the date of last known follow-up alive without clinical progression.; Clinical evidence of disease progression includes evidence of progression or recurrence on imaging, clinical examination, development of symptoms attributable to cancer progression, or initiation of other anticancer treatment for prostate cancer.	5 years
Secondary	Time to subsequent hormonal therapy	Time to subsequent hormone therapy is the interval from randomisation to the first date that androgen deprivation therapy is recommenced for the treatment of recurrent (or progressive) prostate cancer, or the date of last known follow-up without recommencement of androgen deprivation therapy.	5 years
Secondary	Time to castration-resistant disease (PCWG2 criteria)	Castration resistant prostate cancer (CRPC) is defined, per PCWG2, by a rising PSA that is greater than 2ng/mL higher than the most recent nadir with a testosterone < 50 ng/dL (<1.7 nmol/L); the rise has to be at least 25% over the most recent nadir; and, the rise has to be confirmed by a second PSA at least three weeks later. The time to castration-resistant prostate cancer is defined as the interval from randomisation to the date that the PSA first met the criteria defined above (i.e. the date of the first PSA to meet these criteria, not the date of the subsequent confirmatory test), or the date of last known follow-up without CRPC.	5 years
Secondary	Safety (adverse events - CTCAE v4.03)	The NCI Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events occurring until 30 days after the last dose of study treatment.	5 years
Secondary	Health related quality of life (HRQL)	HRQL will be reported by participants using the EORTC core quality of life questionnaire (QLQ C-30) and prostate cancer specific module (PR-25). The EQ-5D-5L will be used to derive utility scores suitable for quality adjusted survival analyses	5 years
Secondary	Health outcomes relative to costs (incremental cost effectiveness ratio)	Information on the following areas of health-care resource usage will be collected: hospitalisations, visits to health professionals, and medications. Quality-adjusted survival (QAS) time will be used to quantify the incremental effectiveness of adding enzalutamide to standard treatment.	5 years

External Links

•   Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group.
•   Australian New Zealand Clinical Trials Registry (ANZCTR)
•   University of Sydney, National Health and Medical Research Council (NHMRC) Clinical Trials Centre.