Clinical trial NCT04136353: Darolutamide Augments Standard Therapy for Localised Very High-Risk Cancer of the Prostate
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: clinically localised prostate cancer
very high risk
darolutamide
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: Australian and New Zealand Urogenital and Prostate Cancer Trials Group
name: Bayer
name: Cancer Trials Ireland
name: Canadian Cancer Trials Group
name: Memorial Sloan Kettering Cancer Center
name: Prostate Cancer Clinical Trials Consortium
First posted: 2019-10-23
Enrollment: 1100
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the prostate
2. 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.
3. 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
4. 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)
5. Adequate renal function: calculated creatinine clearance \> 30 mL/min (Cockroft-Gault)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1
7. Study treatment both planned and able to start within 7 days after randomisation
8. Willing to complete health-related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision
9. Willing and able to comply with all study requirements, including standard of care treatment such as EBRT, timing and/or nature of required assessments
10. Signed, written informed consent

    Exclusion Criteria:
11. Prostate cancer with predominant non-adenocarcinoma features (sarcomatoid or spindle cell or neuroendocrine small cell or squamous cell components or other non-adenocarcinoma)
12. 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).
13. 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.
14. PSA \> 100 ng/mL at any time
15. Any prior use of new generation potent AR inhibition (abiraterone, enzalutamide, apalutamide, darolutamide or similar agents).
16. 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
17. Bilateral orchidectomy
18. Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields that would preclude the required RT
19. 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.
20. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of darolutamide, including difficulty swallowing tablets
21. 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.
22. 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)
23. 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
24. 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.
25. Participation in other clinical trials of investigational agents for the treatment of prostate cancer or other diseases
26. Major surgery within 21 days prior to randomisation
27. Patients with history of hypersensitivity to the study treatment

Primary outcomes:
measure: Metastasis-free survival
timeFrame: Through study completion, an average of 5 years
Secondary outcomes:
measure: Overall survival
timeFrame: Through study completion, an average of 5 years
measure: Prostate cancer-specific survival
timeFrame: Through study completion, an average of 5 years
measure: PSA-progression free survival
timeFrame: Through study completion, an average of 5 years
measure: Time to subsequent hormonal therapy
timeFrame: Through study completion, an average of 5 years
measure: Time to castration-resistance
timeFrame: Through study completion, an average of 5 years
measure: Frequency and severity of adverse events (CTCAE v5.0, RTOG/EORTC acute/late radiation morbidity criteria)
timeFrame: Approximately 12-weekly for 2 years from randomisation until 30 days after the last dose of study treatment.
measure: Health-related quality of life
timeFrame: Through study completion, an average of 5 years
measure: Fear of cancer recurrence
timeFrame: Through study completion, an average of 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Brighton
country: United States
facility: Dana Farber Cancer Institute - St. Elizabeth's
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital and Medical Center
state: Massachusetts
city: Milford
country: United States
facility: Dana Farber Cancer Institute - Milford
state: Massachusetts
city: Omaha
country: United States
facility: XCancer Omaha/Urology Cancer Center
state: Nebraska
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Clifton
country: United States
facility: New Jersey Urology Saddle Brook
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Voorhees
country: United States
facility: New Jersey Urology Voorhees
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology and Hematology Specialists
state: New Mexico
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: Mineola
country: United States
facility: New York University Langone Long Island
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: Kettering
country: United States
facility: Dayton Physicians Network
state: Ohio
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: GenesisCare Newcastle
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Nowra
country: Australia
facility: Shoalhaven District Memorial Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St Vincent's Public Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Sydney
country: Australia
facility: Northern Cancer Institute
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St George Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Campbelltown hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: ROPART
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Southport
country: Australia
facility: Icon Cancer Centre
state: Queensland
city: Townsville
country: Australia
facility: Townsville Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Kurralta Park
country: Australia
facility: Ashford Cancer Centre Research
state: South Australia
city: Hobart
country: Australia
facility: Icon Cancer Centre Hobart
state: Tasmania
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Peter MacCallum Cancer Centre - Bendigo Campus
state: Victoria
city: Bentleigh East
country: Australia
facility: Peter MacCallum Cancer Centre (Moorabbin Campus)
state: Victoria
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Malvern
country: Australia
facility: GenesisCare Cabrini (Gandel Wing), Cabrini Hospital Malvern
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Traralgon
country: Australia
facility: Latrobe Regional Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Surrey
country: Canada
facility: BC Cancer Agency (BCCA) Fraser Valley
state: British Columbia
city: Brandon
country: Canada
facility: Western Manitoba Cancer Centre - Prairie Mountain Health
state: Manitoba
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Saint John
country: Canada
facility: Regional Health Authority B, Zone 2 Saint John Regional Hospital
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre, St. John's
state: Newfoundland and Labrador
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Ontario
city: Sault Ste Marie
country: Canada
facility: Sault Area Hospital - Algoma District Cancer Program
state: Ontario
city: Toronto
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre - Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Greenfield Park
country: Canada
facility: Centre Integre de Sante et de Services Sociaux de la Monteregie Centre
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Québec
country: Canada
facility: Hôtel-Dieu de Québec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Quebec
country: Canada
facility: Centre Hospitalier Regional de Trois-Rivieres
city: Rathgar
country: Ireland
facility: St. Luke's Hospital
state: Dublin 6
city: Cork
country: Ireland
facility: Cork University Hospital
city: Cork
country: Ireland
facility: Bon Secours Hospital Cork in association with UPMC Hillman Centre
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Dublin
city: Dublin
country: Ireland
facility: St Luke's Radiation Oncology Network at St James's Hospital
city: Dublin
country: Ireland
facility: Beacon Private Hospital Dublin
city: Dublin
country: Ireland
facility: Tallaght University Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital Bath
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Guy's and St Thomas Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - Nottingham City Hospital
Study officials:
affiliation: Dana-Farber Cancer Institute and Harvard Medical School
name: Christopher Sweeney
role: STUDY_CHAIR
affiliation: Jewish General Hospital and McGill University
name: Tamim Niazi
role: STUDY_CHAIR
References: