DASL-HiCaP: Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate

Sponsor

University of Sydney (Other)

Overall Status

Recruiting

CT.gov ID

NCT04136353

Collaborator

Australian and New Zealand Urogenital and Prostate Cancer Trials Group (Other), Bayer (Industry), Cancer Trials Ireland (Other), Canadian Cancer Trials Group (Other), Memorial Sloan Kettering Cancer Center (Other), Prostate Cancer Clinical Trials Consortium (Other)

1,100

Enrollment

Locations

Arms

100

Anticipated Duration (Months)

14.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Darolutamide Drug: Placebo oral tablet Drug: Luteinizing Hormone-Releasing Hormone Analog Radiation: External Beam Radiotherapy	Phase 3

Detailed Description

This trial aims to demonstrate that the use of darolutamide (in addition to standard of care) will be more effective than current standard of care in enhancing the ability of prostate or prostate bed radiation and 96 weeks of androgen suppression in decreasing the number of patients who develop metastases and subsequently die of prostate cancer. Darolutamide is a novel antagonist of the AR with favourable tolerability due to negligible penetration of the blood-brain barrier. Emergence of metastatic disease is the lethal event after local therapy, either with prostatectomy or definitive radiation. Augmenting adjuvant systemic therapy (either ADT or ADT plus docetaxel) with darolutamide has the potential to eradicate micrometastatic disease after either type of local therapy and decrease the death rate from prostate cancer.

This pragmatic design incorporates current standard of care for all patients and the option for docetaxel to be added to ADT. As such, the data will be applicable for all patients with very high risk prostate cancer treated with local therapy and will be the first study incorporating docetaxel use as one of the standard of care options. Even if docetaxel is definitively proven to improve MFS and OS in the adjuvant setting, not all patients will be fit for docetaxel. This will be the first trial that has the potential to build upon current and future advances that may emerge and be the most effective strategy to decrease death rate from prostate cancer in the near term if it further augments docetaxel efficacy in chemo-fit patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

DASL-HiCaP: Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate (ANZUP1801): A Randomised Phase 3 Double-blind, Placebo-controlled Trial of Adding Darolutamide to Androgen Deprivation Therapy and Definitive or Salvage Radiation in Very High Risk, Clinically Localised Prostate Cancer

Actual Study Start Date :

Mar 31, 2020

Anticipated Primary Completion Date :

Jan 31, 2028

Anticipated Study Completion Date :

Jul 31, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Darolutamide Darolutamide 600mg (2 x 300mg tablets) twice daily by mouth for 96 weeks, adherence monitored by participant report. All participants are treated with an LHRHA for 96 weeks from randomisation and external beam radiation therapy started within 8-24 weeks after randomisation.	Drug: Darolutamide 2 x 300mg oral tablets twice daily for 96 weeks Drug: Luteinizing Hormone-Releasing Hormone Analog All participants are to receive standard background therapy with an LHRHA, as per standard of care. The choice of LHRHA is at the discretion of the treating clinician. Radiation: External Beam Radiotherapy All participants are to receive standard background therapy with curative-intent RT to the prostate or prostate bed as well as the pelvic lymph nodes using EBRT.
Placebo Comparator: Placebo Placebo (2 tablets) twice daily by mouth for 96 weeks, adherence monitored by participant report. All participants are treated with an LHRHA for 96 weeks from randomisation and external beam radiation therapy started within 8-24 weeks after randomisation.	Drug: Placebo oral tablet 2 oral tablets twice daily for 96 weeks Drug: Luteinizing Hormone-Releasing Hormone Analog All participants are to receive standard background therapy with an LHRHA, as per standard of care. The choice of LHRHA is at the discretion of the treating clinician. Radiation: External Beam Radiotherapy All participants are to receive standard background therapy with curative-intent RT to the prostate or prostate bed as well as the pelvic lymph nodes using EBRT.

Arm

Intervention/Treatment

Experimental: Darolutamide

Darolutamide 600mg (2 x 300mg tablets) twice daily by mouth for 96 weeks, adherence monitored by participant report. All participants are treated with an LHRHA for 96 weeks from randomisation and external beam radiation therapy started within 8-24 weeks after randomisation.

Drug: Darolutamide

2 x 300mg oral tablets twice daily for 96 weeks

Drug: Luteinizing Hormone-Releasing Hormone Analog

All participants are to receive standard background therapy with an LHRHA, as per standard of care. The choice of LHRHA is at the discretion of the treating clinician.

Radiation: External Beam Radiotherapy

All participants are to receive standard background therapy with curative-intent RT to the prostate or prostate bed as well as the pelvic lymph nodes using EBRT.

Placebo Comparator: Placebo

Placebo (2 tablets) twice daily by mouth for 96 weeks, adherence monitored by participant report. All participants are treated with an LHRHA for 96 weeks from randomisation and external beam radiation therapy started within 8-24 weeks after randomisation.

Drug: Placebo oral tablet

2 oral tablets twice daily for 96 weeks

Drug: Luteinizing Hormone-Releasing Hormone Analog

All participants are to receive standard background therapy with an LHRHA, as per standard of care. The choice of LHRHA is at the discretion of the treating clinician.

Radiation: External Beam Radiotherapy

All participants are to receive standard background therapy with curative-intent RT to the prostate or prostate bed as well as the pelvic lymph nodes using EBRT.

Outcome Measures

Primary Outcome Measures

Metastasis-free survival [Through study completion, an average of 5 years]
Evidence of metastases includes findings on WBBS or CT or MRI (as reported by the site investigator) that are either characteristic of metastatic prostate cancer, and/or confirmed by other test results e.g. cytology or histopathology.

Secondary Outcome Measures

Overall survival [Through study completion, an average of 5 years]
Overall survival 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.
Prostate cancer-specific survival [Through study completion, an average of 5 years]
Prostate cancer-specific survival is defined as the interval from the date of randomisation to the date of last known follow-up alive, or the date of death from prostate cancer. Deaths from other causes will be summarised.
PSA-progression free survival [Through study completion, an average of 5 years]
For participants who receive definitive radiotherapy (i.e. without radical prostatectomy), PSA progression is defined by the Phoenix criteria (requires confirmation by a repeat PSA performed at least 3 weeks later). For participants who have undergone a radical prostatectomy, an increase in PSA of >0.2 ng/mL above the nadir would be considered PSA progression (requires confirmation by a repeat PSA performed at least 3 weeks later).
Time to subsequent hormonal therapy [Through study completion, an average of 5 years]
Time to subsequent hormone therapy is the interval from randomisation to the first date that endocrine therapy is recommenced or changed for the treatment of recurrent (or progressive) prostate cancer.
Time to castration-resistance [Through study completion, an average of 5 years]
Defined according to the PCWG3 criteria. If a participant has radiographic progression without serological progression, this will also be deemed castration resistant prostate cancer
Frequency and severity of adverse events (CTCAE v5.0, RTOG/EORTC acute/late radiation morbidity criteria) [Approximately 12-weekly for 2 years from randomisation until 30 days after the last dose of study treatment.]
Safety reporting will describe the frequency and severity of AEs. The CTCAE v5.0 will be used to classify and grade the intensity of AEs occurring until 30 days after the last dose of study treatment. The RTOG/EORTC Scoring Criteria will be used to assess morbidities related to radiation therapy (RT) until 6 years after randomisation. Acute AEs are those occurring within 90 days after starting RT, and will be classified and graded according to the RTOG/EORTC Acute Radiation Morbidity Scoring Criteria. Late AEs are those occurring more than 90 days after starting RT, and will be classified and rated according to the RTOG/EORTC Late Radiation Morbidity Scoring Schema.
Health-related quality of life [Through study completion, an average of 5 years]
EORTC Core Quality of Life Questionnaire (QLQC-30). Importance of quality of life issues are assessed using a four-point scale (1 = not at all, 4 = very much) EORTC Quality of Life Questionnaire for Prostate Cancer (PR-25). Importance of quality of life issues are assessed using a four-point scale (1 = not at all, 4 = very much) Euroqol 5 item preference-based measure of health (EQ-5D-5L), comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100.
Fear of cancer recurrence [Through study completion, an average of 5 years]
Using the Fear of Cancer Recurrence Inventory (FCRI), a 42-item questionnaire with scores of 0 (never/not at all) - 4 (all the time/a great deal) for each.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the prostate
EITHER planned for primary RT and judged to be at very high risk for recurrence based on any of the following:

Grade Group 5, OR
Grade Group 4 AND one or more of the following: clinical T2b-4 OR MRI with seminal vesicle invasion OR extracapsular extension OR PSA* > 20ng/mL, OR
Pelvic nodal involvement (involvement of lymph nodes (LNs) at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm) OR

Post-radical prostatectomy ≤ 365 days prior to randomisation and planned for RT with PSA* ≥ 0.1 ng/mL that has risen or remained stable (within ≤ 0.05 ng/mL) since a previous level at least 1 week earlier, judged to be at very high risk for recurrence based on any of the following:

Grade Group 5, OR
Grade Group 4 AND pT3a or higher, OR
Pelvic nodal involvement (involvement of LNs at or below the bifurcation of the aorta into the common iliac arteries) defined radiologically as greater than 10mm on short axis using standard CT or MRI, or pathologically confirmed (PSMA PET alone is not considered enough if ≤ 10mm) * This PSA level must be measured within 60 days prior to randomisation. However, if a participant has already commenced endocrine therapy (ET) for prostate cancer, this PSA level must be measured within 180 days prior to commencing ET.

Adequate bone marrow function: Haemoglobin ≥ 100g/L, white cell count (WCC) ≥ 4.0x109/L, absolute neutrophil count (ANC) ≥ 1.5x109/L and platelets > 100 x 109/L
Adequate liver function: alanine aminotransferase (ALT) < 2 x upper limit of normal (ULN) and total bilirubin < 1.5 x ULN, (or if total bilirubin is between 1.5 - 2 x ULN, they must have a normal conjugated bilirubin)
Adequate renal function: calculated creatinine clearance > 30 mL/min (Cockroft-Gault)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
Study treatment both planned and able to start within 7 days after randomisation
Willing to complete health-related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision
Willing and able to comply with all study requirements, including standard of care treatment such as EBRT, timing and/or nature of required assessments
Signed, written informed consent

Exclusion Criteria:

Prostate cancer with predominant non-adenocarcinoma features (sarcomatoid or spindle cell or neuroendocrine small cell or squamous cell components or other non-adenocarcinoma)
Involvement of LNs by conventional CT imaging superior to the common iliac artery bifurcation, and/or outside the pelvis (distant LNs). LN involvement is defined by histopathological confirmation, or by a short axis measurement > 10mm on standard imaging (CT or MRI, but not PET).
Evidence of metastatic disease. Minimum imaging requirements to exclude metastatic disease are diagnostic quality imaging of both the pelvis and the abdomen (CT or MRI), chest (CXR or CT), and a whole body radioisotope bone scan (WBBS).

If endocrine therapy (ET) had not started, imaging must be within 60 days prior to randomisation.
If ET has been started, imaging must have been performed no more than 60 days prior to starting ET and no more than 30 days after starting ET and prior to randomisation.

PSA > 100 ng/mL at any time
Any prior use of new generation potent AR inhibition (abiraterone, enzalutamide, apalutamide, darolutamide or similar agents).
Prior endocrine therapy for prostate cancer except for the following which are allowed:

(i) LHRHA and/or (ii) a first-generation nonsteroidal antiandrogen (NSAA) are allowed if commenced no more than 90 days before randomisation. If an NSAA has been used, it must be stopped before starting study treatment with darolutamide/placebo; and
Prior use of 5-alpha reductase inhibitor is allowed and if used it must be stopped before starting study treatment with darolutamide/placebo

Bilateral orchidectomy
Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields that would preclude the required RT
History of

Loss of consciousness or transient ischemic attack or stroke within 6 months prior to randomisation, or
Significant cardiovascular disease within 6 months prior to randomisation: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater), ongoing arrhythmias of Grade > 2 (CTCAE v5.0), thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism), coronary artery bypass graft. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.

Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of darolutamide, including difficulty swallowing tablets
History of another malignancy within 5 years prior to randomisation except for those malignancies treated with curative intent with a predicted risk of relapse of less than 10% including but not limited to non-melanoma carcinoma of the skin; or adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours). All such cases with a history of malignancy within the last 5 years are to be discussed with study team before randomisation. Melanoma in-situ and other adequately treated in-situ neoplasms are not considered malignancies for the purposes of eligibility assessment.
Concurrent illness, including severe infection that might jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety (HIV infection is not an exclusion criterion if it is controlled with anti-retroviral drugs that are unaffected by concomitant darolutamide)
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
Patients who are sexually active with women of child-bearing potential and not willing/able to use medically acceptable and highly effective forms of contraception during study treatment and for at least 4 weeks after completion of study treatment.

Contraception must include:

Condom use (also required if sexual partner is pregnant), and
Additional birth control with low failure rate (less than 1% per year) when used consistently and correctly. E.g. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, true sexual abstinence.

True sexual abstinence will only be an acceptable form of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to study treatment, and withdrawal are not acceptable methods of contraception.

Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases
Major surgery within 21 days prior to randomisation
Patients with history of hypersensitivity to the study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
2	Dana Farber Cancer Institute - St. Elizabeth's	Brighton	Massachusetts	United States	02135
3	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
4	Dana Farber Cancer Institute - Milford	Milford	Massachusetts	United States	01757
5	GU Research Network	Omaha	Nebraska	United States	68130
6	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States	07920
7	Memorial Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
8	Memorial Sloan Kettering Bergen	Montvale	New Jersey	United States	07645
9	New Mexico Oncology and Hematology Specialists	Albuquerque	New Mexico	United States	87109
10	Memorial Sloan Kettering Commack	Commack	New York	United States	11725
11	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
12	New York University Langone Medical Center	New York	New York	United States	10016
13	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
14	Memorial Sloan Kettering Nassau	Uniondale	New York	United States	11553
15	Dayton Physicians Network	Kettering	Ohio	United States	45409
16	Border Medical Oncology Research Unit	Albury	New South Wales	Australia	2640
17	Gosford Hospital	Gosford	New South Wales	Australia	2250
18	GenesisCare Newcastle	Newcastle	New South Wales	Australia	2290
19	Calvary Mater Newcastle	Newcastle	New South Wales	Australia	2298
20	Shoalhaven District Memorial Hospital	Nowra	New South Wales	Australia	2541
21	St Vincent's Public Hospital	Sydney	New South Wales	Australia	2010
22	Prince of Wales Hospital	Sydney	New South Wales	Australia	2031
23	Chris O'Brien Lifehouse	Sydney	New South Wales	Australia	2050
24	Northern Cancer Institute	Sydney	New South Wales	Australia	2065
25	Sydney Adventist Hospital	Sydney	New South Wales	Australia	2076
26	Liverpool Hospital	Sydney	New South Wales	Australia	2170
27	St George Hospital	Sydney	New South Wales	Australia	2217
28	Campbelltown hospital	Sydney	New South Wales	Australia	2560
29	Wollongong Hospital	Wollongong	New South Wales	Australia	2500
30	ROPART	Brisbane	Queensland	Australia	4101
31	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
32	Icon Cancer Centre	Southport	Queensland	Australia	4215
33	Townsville Hospital	Townsville	Queensland	Australia	4814
34	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
35	Ashford Cancer Centre Research	Kurralta Park	South Australia	Australia	5037
36	Icon Cancer Centre Hobart	Hobart	Tasmania	Australia	7000
37	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
38	Peter MacCallum Cancer Centre - Bendigo Campus	Bendigo	Victoria	Australia	3550
39	Peter MacCallum Cancer Centre (Moorabbin Campus)	Bentleigh East	Victoria	Australia	3165
40	Box Hill Hospital	Box Hill	Victoria	Australia	3128
41	GenesisCare Cabrini (Gandel Wing), Cabrini Hospital Malvern	Malvern	Victoria	Australia	3144
42	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
43	The Alfred Hospital	Melbourne	Victoria	Australia	3004
44	Sunshine Hospital	St Albans	Victoria	Australia	3021
45	Latrobe Regional Hospital	Traralgon	Victoria	Australia
46	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6143
47	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6006
48	Western Manitoba Cancer Centre - Prairie Mountain Health	Brandon	Manitoba	Canada	R7A 2B3
49	Regional Health Authority B, Zone 2 Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
50	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
51	Queen Elizabeth II Health Sciences Centre	London	Ontario	Canada	B3H 1V7
52	Sault Area Hospital - Algoma District Cancer Program	Sault Ste Marie	Ontario	Canada	P6B 0A8
53	Ottawa Hospital Research Institute	Toronto	Ontario	Canada	K1H 8L6
54	Odette Cancer Centre - Sunnybrook Hospital	Toronto	Ontario	Canada	M4N 3M5
55	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
56	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec	Canada
57	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
58	Hôtel-Dieu de Québec	Québec	Quebec	Canada	G1R 2J6
59	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec	Canada	J1H 5N4
60	Centre Hospitalier Regional de Trois-Rivieres	Quebec		Canada	G8Z 3R9
61	St. Luke's Hospital	Rathgar	Dublin 6	Ireland	D06 E1C9
62	Cork University Hospital	Cork		Ireland	T12 EC8P
63	Bon Secours Hospital Cork in association with UPMC Hillman Centre	Cork		Ireland	T23
64	Mater Misericordiae University Hospital	Dublin		Ireland	D07 A8NN
65	Mater Private Dublin	Dublin		Ireland	D07 WKW8
66	Auckland City Hospital	Auckland		New Zealand	1023
67	Christchurch Hospital	Christchurch		New Zealand	8011
68	Palmerston North Hospital	Palmerston North		New Zealand	4442
69	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
70	William Harvey Hospital	Ashford		United Kingdom	TN24 0LZ
71	Kent and Canterbury Hospital	Canterbury		United Kingdom	CT1 3NG
72	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
73	Guy's and St Thomas Hospital	London		United Kingdom	SE1 9RT
74	Royal Marsden Hospital	London		United Kingdom
75	Nottingham University Hospitals NHS Trust - Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB

Sponsors and Collaborators

University of Sydney
Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Bayer
Cancer Trials Ireland
Canadian Cancer Trials Group
Memorial Sloan Kettering Cancer Center
Prostate Cancer Clinical Trials Consortium

Investigators

Study Chair: Christopher Sweeney, Dana-Farber Cancer Institute and Harvard Medical School
Study Chair: Tamim Niazi, Jewish General Hospital and McGill University