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

• Sponsor: University of Sydney (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02446444
• Collaborator: Australian and New Zealand Urogenital and Prostate Cancer Trials Group (Other), National Health and Medical Research Council, Australia (Other), Cancer Trials Ireland (Other), TROG- Trans Tasman Radiation Oncology Group (Other), European Organisation for Research and Treatment of Cancer - EORTC (Other)
• Enrollment: 802
• Locations: 69
• Arms: 2
• Duration (Months): 124
• Patients Per Site: 11.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Prostatic Neoplasms	Drug: Enzalutamide; Drug: Conventional NSAA; Drug: LHRHA; Radiation: External Beam Radiotherapy (78 Gy in 39 fractions or 46 Gy in 23 fractions plus brachytherapy boost)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 802 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Stratification Factors: Gleason score (<=7 versus 8-10), Regional lymph nodes involvement (N0 versus N1) Clinical T-stage (T2 and below versus T3 and above), PSA (<20ng/mL versus ≥ 20ng/mL) Study Site Brachytherapy (yes versus no) Pelvic Field (yes versus no)Stratification Factors:Gleason score (<=7 versus 8-10), Regional lymph nodes involvement (N0 versus N1) Clinical T-stage (T2 and below versus T3 and above), PSA (<20ng/mL versus ≥ 20ng/mL) Study Site Brachytherapy (yes versus no) Pelvic Field (yes versus no)
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomised Phase 3 Trial of Enzalutamide in Androgen Deprivation Therapy With Radiation Therapy for High Risk, Clinically Localised, Prostate Cancer: ENZARAD
• Study Start Date: Mar 1, 2014
• Anticipated Primary Completion Date: Dec 1, 2023
• Anticipated Study Completion Date: Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzalutamide Enzalutamide 160 mg daily, by mouth, for 24 months from randomisation. All participants are treated with a LHRHA for 24 months from randomisation and external beam radiation therapy started approximately 16 weeks after randomisation (+/- brachytherapy boost)	Drug: Enzalutamide; Drug: LHRHA; Radiation: External Beam Radiotherapy (78 Gy in 39 fractions or 46 Gy in 23 fractions plus brachytherapy boost)
Active Comparator: Conventional Non-steroidal Anti-androgen (NSAA) Conventional Non-steroidal Anti-androgen (NSAA), by mouth, for 6 months from randomisation. All participants are treated with a LHRHA for 24 months from randomisation and external beam radiation therapy started approximately 16 weeks after randomisation (+/- brachytherapy boost)	Drug: Conventional NSAA; Drug: LHRHA; Radiation: External Beam Radiotherapy (78 Gy in 39 fractions or 46 Gy in 23 fractions plus brachytherapy boost)

Outcome Measures

Primary Outcome Measures

1. Metastasis-free survival [5 years]

   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

Secondary Outcome Measures

1. Overall survival [5 years]

   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.

2. Prostate cancer-specific survival [5 years]

   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.

3. PSA (Prostate-Specific Antigen) progression-free survival [5 years]

   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.

4. Clinical progression-free survival [5 years]

   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. Time to subsequent hormonal therapy [5 years]

   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.

6. Time to castration-resistant disease (PCWG2 criteria) [5 years]

   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.

7. Safety (adverse events - CTCAE v4.03) [5 years]

   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.

8. Health related quality of life (HRQL) [5 years]

   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

9. Health outcomes relative to costs (incremental cost effectiveness ratio) [5 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

1. Age ≥18 years

2. Adequate bone marrow function Haemoglobin (Hb) ≥100g/L and White Cell Count (WCC) ≥ 4.0 x 109/L and platelets ≥100 x 109/L

3. 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).

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

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

6. Study treatment both planned and able to start within 7 days of randomisation.

7. Willing and able to comply with all study requirements, including treatment, and attending required assessments

8. Has completed the baseline HRQOL questionnaires UNLESS is unable to complete because of literacy or limited vision

9. 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.

1. 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

2. PSA > 100 ng/mL

3. 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).

4. 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.

1. 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;

2. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception.

3. 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.

1. Bilateral orchidectomy or radical prostatectomy

2. Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields

3. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases.

4. Major surgery within 21 days prior to randomisation

5. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of enzalutamide, including difficulty swallowing tablets

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
2	Beth Israel Deaconness Medical Center	Boston	Massachusetts	United States	02215
3	Blacktown Hospital	Blacktown	New South Wales	Australia	2148
4	Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
5	Chris O'Brien Lifehouse	Camperdown	New South Wales	Australia	2050
6	Genesis Cancer Care Newcastle	Gateshead	New South Wales	Australia	2290
7	Gosford Hospital	Gosford	New South Wales	Australia	2250
8	St George Hospital	Kogarah	New South Wales	Australia	2217
9	Liverpool Hospital	Liverpool	New South Wales	Australia	2170
10	Orange Health Service	Orange	New South Wales	Australia	2800
11	Prince of Wales Hospital	Randwick	New South Wales	Australia	2131
12	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
13	St Vincent's Hospital	Sydney	New South Wales	Australia	2010
14	Tamworth Rural Referral Hospital	Tamworth	New South Wales	Australia	2340
15	Sydney Adventist Hospital	Wahroonga	New South Wales	Australia	2076
16	Calvary Mater Newcastle	Waratah	New South Wales	Australia	2298
17	Westmead Hospital	Westmead	New South Wales	Australia	2145
18	Wollongong Hospital	Wollongong	New South Wales	Australia	2500
19	Genesis Cancer Care Queensland - Wesley and Chermside	Auchenflower	Queensland	Australia	4066
20	Townsville Hospital	Douglas	Queensland	Australia	4814
21	Royal Brisbane & Womens Hospital	Herston	Queensland	Australia	4006
22	Nambour General Hospital	Nambour	Queensland	Australia	4560
23	Radiation Oncology Services Mater Centre	South Brisbane	Queensland	Australia	4101
24	ICON - Gold Coast (formerly ROC Gold Coast)	Southport	Queensland	Australia	4215
25	ICON - Toowoomba (formerly ROC Toowoomba)	Toowoomba	Queensland	Australia	4350
26	Genesis Cancer Care Queensland - Tugun and Southport	Tugun	Queensland	Australia	4224
27	Princess Alexandra Hospital Brisbane	Woolloongabba	Queensland	Australia	4102
28	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
29	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
30	Ashford Cancer Centre Research (Adelaide Cancer Centre)	Kurralta Park	South Australia	Australia	5037
31	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
32	Peter MacCallum Cancer Centre	Bendigo	Victoria	Australia	3550
33	Peter MacCallum Cancer Centre (Moorabbin Campus)	Bentleigh East	Victoria	Australia	3165
34	Eastern Health (Box Hill Hospital)	Box Hill	Victoria	Australia	3128
35	Genesis Care - Epping (formerly EROC)	Epping	Victoria	Australia	3076
36	Genesis Care - Western (formerly WROC)	Footscray	Victoria	Australia	3011
37	Genesis Care - Frankston (formerly FROC)	Frankston	Victoria	Australia	3199
38	Austin Health	Heidelberg	Victoria	Australia	3084
39	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3002
40	Epworth HealthCare - Richmond	Richmond	Victoria	Australia	3121
41	Genesis Care - Ringwood (formerly RROC)	Ringwood East	Victoria	Australia	3135
42	Sunshine Hospital	St Albans	Victoria	Australia	3021
43	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6149
44	Salzburger Landeskliniken - Universitätsklinikum Salzburg	Salzburg		Austria	5020
45	AZ Groeninge Kortrijk- Campus Kennedylaan	Kortrijk		Belgium	8500
46	Cork University Hospital	Cork	Co Cork	Ireland
47	Galway University Hospital	Galway	Co Galway	Ireland
48	Mater Misericordiae University Hospital	Dublin	Dublin 7	Ireland	Dublin 7
49	Beacon Private Hospital	Dublin		Ireland	Dublin 18
50	St Luke's Hospital	Dublin		Ireland	Dublin 6
51	Mater Private Hospital	Dublin		Ireland	Dublin 7
52	Auckland City Hospital	Auckland		New Zealand	1142
53	Christchurch Hospital	Christchurch		New Zealand	4170
54	Palmerston North Hospital	Palmerston North		New Zealand	4442
55	The Institute Of Oncology	Ljubljana		Slovenia	1000
56	Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)	Badalona	Barcelona	Spain	08916
57	Hospital Donostia	Donostia	Gipuzkoa	Spain	20014
58	Hospital Universitario de Salamanca	Salamanca		Spain	37007
59	Velindre Hospital	Whitchurch	Cardiff	United Kingdom	CF14 2TL
60	University Hospital Southhampton	Southampton	Hampshire	United Kingdom	SO16 6YD
61	Kent and Canterbury Hospital	Canterbury	Kent	United Kingdom	CT1 3NG
62	Royal Marsden Hospital	Chelsea	London	United Kingdom	SW3 6JJ
63	Western General Hospital	Edinburgh	Scotland	United Kingdom	EH4 2XU
64	Royal United Hospital Bath	Bath		United Kingdom	BA1 3NG
65	Addenbrookes Hospital	Cambridge		United Kingdom
66	University of London Hospital	London		United Kingdom	NW1 2BU
67	Guys and St Thomas Hospital	London		United Kingdom	SE1 9RT
68	Charring Cross Hospital: Imperial College Healthcare NHS Trust	London		United Kingdom	W6 8RF
69	Nottingham City Hospital- City Campus	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

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

Investigators

• Study Chair: Scott Williams, ANZUP and Peter MacCallum Cancer Centre
• Study Chair: Paul Nguyen, Dana Farber Cancer Institute and ANZUP

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: University of Sydney
• ClinicalTrials.gov Identifier: NCT02446444
• Other Study ID Numbers: ANZUP1303; ACTRN12614000126617
• First Posted: May 18, 2015
• Last Update Posted: Apr 2, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by University of Sydney: High risk; clinically localised prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

No Results Posted as of Apr 2, 2021