Prostate Cancer Clinical Trial

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

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.

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Full 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.

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Eligibility Criteria

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

Study is for people with:

Prostate Cancer

Phase:

Phase 3

Estimated Enrollment:

1100

Study ID:

NCT04136353

Recruitment Status:

Recruiting

Sponsor:

University of Sydney

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There are 82 Locations for this study

See Locations Near You

Dana-Farber Cancer Institute
Boston Massachusetts, 02215, United States More Info
Christopher Sweeney
Principal Investigator
Dana Farber Cancer Institute - St. Elizabeth's
Brighton Massachusetts, 02135, United States More Info
Christopher Sweeney
Principal Investigator
Lahey Hospital and Medical Center
Burlington Massachusetts, 01805, United States More Info
Brendan Connell
Principal Investigator
Dana Farber Cancer Institute - Milford
Milford Massachusetts, 01757, United States More Info
Christopher Sweeney
Principal Investigator
GU Research Network
Omaha Nebraska, 68130, United States More Info
Luke Nordquist, MD
Principal Investigator
Memorial Sloan Kettering Basking Ridge
Basking Ridge New Jersey, 07920, United States More Info
Sean McBride, MD
Principal Investigator
Memorial Sloan Kettering Monmouth
Middletown New Jersey, 07748, United States More Info
Sean McBride, MD
Principal Investigator
Memorial Sloan Kettering Bergen
Montvale New Jersey, 07645, United States More Info
Sean McBride, MD
Principal Investigator
New Mexico Oncology and Hematology Specialists
Albuquerque New Mexico, 87109, United States More Info
Jose W Avitia, MD
Principal Investigator
Memorial Sloan Kettering Commack
Commack New York, 11725, United States More Info
Sean McBride, MD
Principal Investigator
Memorial Sloan Kettering Westchester
Harrison New York, 10604, United States More Info
Sean McBride, MD
Principal Investigator
New York University Langone Medical Center
New York New York, 10016, United States More Info
David Wise, MD
Principal Investigator
Memorial Sloan Kettering Cancer Center
New York New York, 10065, United States More Info
Sean McBride, MD
Principal Investigator
Memorial Sloan Kettering Nassau
Uniondale New York, 11553, United States More Info
Sean McBride, MD
Principal Investigator
Dayton Physicians Network
Kettering Ohio, 45409, United States More Info
Kelly Miller, MD
Principal Investigator
Seattle Cancer Care Alliance
Seattle Washington, 98109, United States More Info
Robert B Montgomery, MD
Principal Investigator
Border Medical Oncology Research Unit
Albury New South Wales, 2640, Australia More Info
Christopher Steer
Principal Investigator
Gosford Hospital
Gosford New South Wales, 2250, Australia More Info
Craig Kukard
Principal Investigator
GenesisCare Newcastle
Newcastle New South Wales, 2290, Australia More Info
Jarad Martin
Principal Investigator
Calvary Mater Newcastle
Newcastle New South Wales, 2298, Australia More Info
Jarad Martin
Principal Investigator
Shoalhaven District Memorial Hospital
Nowra New South Wales, 2541, Australia More Info
Senthikumar Gandhidasan
Principal Investigator
St Vincent's Public Hospital
Sydney New South Wales, 2010, Australia More Info
Anthony Joshua
Principal Investigator
Prince of Wales Hospital
Sydney New South Wales, 2031, Australia More Info
Colin Chen
Principal Investigator
Chris O'Brien Lifehouse
Sydney New South Wales, 2050, Australia More Info
Leily Crezaei
Principal Investigator
Northern Cancer Institute
Sydney New South Wales, 2065, Australia More Info
Laurence Krieger
Principal Investigator
Sydney Adventist Hospital
Sydney New South Wales, 2076, Australia More Info
Amy Teh
Principal Investigator
Liverpool Hospital
Sydney New South Wales, 2170, Australia More Info
Mark Sidhom
Principal Investigator
St George Hospital
Sydney New South Wales, 2217, Australia More Info
Nadine Beydoun
Principal Investigator
Campbelltown hospital
Sydney New South Wales, 2560, Australia More Info
Felicia Roncolato
Principal Investigator
Wollongong Hospital
Wollongong New South Wales, 2500, Australia More Info
Senthikumar Gandhidasan
Principal Investigator
ROPART
Brisbane Queensland, 4101, Australia More Info
David Pryor
Principal Investigator
Royal Brisbane and Women's Hospital
Herston Queensland, 4029, Australia More Info
Phillip Chan
Principal Investigator
Icon Cancer Centre
Southport Queensland, 4215, Australia More Info
Eric Khoo
Principal Investigator
Townsville Hospital
Townsville Queensland, 4814, Australia More Info
Alexander Tan
Principal Investigator
Princess Alexandra Hospital
Woolloongabba Queensland, 4102, Australia More Info
David Pryor
Principal Investigator
Ashford Cancer Centre Research
Kurralta Park South Australia, 5037, Australia More Info
Francis Parnis
Principal Investigator
Icon Cancer Centre Hobart
Hobart Tasmania, 7000, Australia More Info
Michael Jones, MD
Principal Investigator
Royal Hobart Hospital
Hobart Tasmania, 7000, Australia More Info
Michael Jones
Principal Investigator
Peter MacCallum Cancer Centre - Bendigo Campus
Bendigo Victoria, 3550, Australia More Info
Neetu Tejani
Principal Investigator
Peter MacCallum Cancer Centre (Moorabbin Campus)
Bentleigh East Victoria, 3165, Australia More Info
Scott Williams
Principal Investigator
Box Hill Hospital
Box Hill Victoria, 3128, Australia More Info
Michael Lim Joon
Principal Investigator
GenesisCare Cabrini (Gandel Wing), Cabrini Hospital Malvern
Malvern Victoria, 3144, Australia More Info
Mario Guirrieri
Principal Investigator
Peter MacCallum Cancer Centre
Melbourne Victoria, 3000, Australia More Info
Scott Williams
Principal Investigator
The Alfred Hospital
Melbourne Victoria, 3004, Australia More Info
Jeremy Millar
Principal Investigator
Sunshine Hospital
St Albans Victoria, 3021, Australia More Info
Tristan Molden-Hauer
Principal Investigator
Latrobe Regional Hospital
Traralgon Victoria, , Australia More Info
Jarad Martin
Principal Investigator
Fiona Stanley Hospital
Murdoch Western Australia, 6143, Australia More Info
Tee Sin Lim
Principal Investigator
Sir Charles Gairdner Hospital
Nedlands Western Australia, 6006, Australia More Info
Suki Gill
Principal Investigator
Cross Cancer Institute
Edmonton Alberta, T6G 1, Canada More Info
Brita Danielson, MD
Principal Investigator
BC Cancer Agency (BCCA) Fraser Valley
Surrey British Columbia, V3V 1, Canada More Info
Winkle Kwan, MD
Principal Investigator
Western Manitoba Cancer Centre - Prairie Mountain Health
Brandon Manitoba, R7A 2, Canada More Info
Gokulan Sivananthan, MD
Principal Investigator
CancerCare Manitoba
Winnipeg Manitoba, R3E 0, Canada More Info
Rashmi Koul, MD
Principal Investigator
Regional Health Authority B, Zone 2 Saint John Regional Hospital
Saint John New Brunswick, E2L 4, Canada More Info
Robert Thompson, MD
Principal Investigator
Dr. H. Bliss Murphy Cancer Centre, St. John's
St. John's Newfoundland and Labrador, A1B 3, Canada More Info
Oliver Holmes, MD
Principal Investigator
Kingston Health Sciences Centre
Kingston Ontario, K7L 2, Canada More Info
Robert Siemens, MD
Principal Investigator
Queen Elizabeth II Health Sciences Centre
London Ontario, B3H 1, Canada More Info
Ricardo Rendon, MD
Principal Investigator
Sault Area Hospital - Algoma District Cancer Program
Sault Ste Marie Ontario, P6B 0, Canada More Info
Mohammad Rassouli, MD
Principal Investigator
Ottawa Hospital Research Institute
Toronto Ontario, K1H 8, Canada More Info
Scott Morgan, MD
Principal Investigator
Odette Cancer Centre - Sunnybrook Hospital
Toronto Ontario, M4N 3, Canada More Info
Hans Chung, MD
Principal Investigator
Princess Margaret Cancer Centre
Toronto Ontario, M5G 2, Canada More Info
Srinivas Raman, MD
Principal Investigator
Centre Integre de Sante et de Services Sociaux de la Monteregie Centre
Greenfield Park Quebec, J4V 2, Canada More Info
Georges Wakil, MD
Principal Investigator
Centre Hospitalier de l'Universite de Montreal
Montreal Quebec, , Canada More Info
Marie-Claude Beauchemin
Principal Investigator
Jewish General Hospital
Montréal Quebec, H3T 1, Canada More Info
Tamim Niazi, MD
Principal Investigator
Hôtel-Dieu de Québec
Québec Quebec, G1R 2, Canada More Info
Andre-guy Martin, MD
Principal Investigator
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke Quebec, J1H 5, Canada More Info
Annie Ebacher, MD
Principal Investigator
Allan Blair Cancer Centre
Regina Saskatchewan, S4T 7, Canada More Info
Nelson Leong, MD
Principal Investigator
Saskatoon Cancer Centre
Saskatoon Saskatchewan, S7N 4, Canada More Info
Duc Le, MD
Principal Investigator
Centre Hospitalier Regional de Trois-Rivieres
Quebec , G8Z 3, Canada More Info
Francois Vincent
Principal Investigator
St. Luke's Hospital
Rathgar Dublin 6, D06 E, Ireland More Info
Gerard McVey
Principal Investigator
Cork University Hospital
Cork , T12 E, Ireland More Info
Mohammad Faisal Jamaluddin
Principal Investigator
Bon Secours Hospital Cork in association with UPMC Hillman Centre
Cork , T23, Ireland More Info
Paul Kelly
Principal Investigator
Mater Misericordiae University Hospital
Dublin , D07 A, Ireland More Info
John McCaffrey
Principal Investigator
Mater Private Dublin
Dublin , D07 W, Ireland More Info
John McCaffrey
Principal Investigator
Beacon Private Hospital Dublin
Dublin , D18 A, Ireland More Info
Alina Mihai, MD
Principal Investigator
Tallaght University Hospital
Dublin , D24 N, Ireland More Info
Ray McDermott, MD
Principal Investigator
Auckland City Hospital
Auckland , 1023, New Zealand More Info
Chakiath Jose
Principal Investigator
Christchurch Hospital
Christchurch , 8011, New Zealand More Info
Ben Hindson
Principal Investigator
Palmerston North Hospital
Palmerston North , 4442, New Zealand More Info
David Peel
Principal Investigator
Aberdeen Royal Infirmary
Aberdeen , AB25 , United Kingdom More Info
Judith Grant
Principal Investigator
William Harvey Hospital
Ashford , TN24 , United Kingdom More Info
Carys Thomas, MD
Principal Investigator
Royal United Hospital Bath
Bath , BA1 3, United Kingdom More Info
Mark Beresford, MD
Principal Investigator
Kent and Canterbury Hospital
Canterbury , CT1 3, United Kingdom More Info
Carys Thomas, MD
Principal Investigator
Beatson West of Scotland Cancer Centre
Glasgow , G12 0, United Kingdom More Info
Carolynn Lamb
Principal Investigator
Guy's and St Thomas Hospital
London , SE1 9, United Kingdom More Info
Simon Hughes
Principal Investigator
Royal Marsden Hospital
London , , United Kingdom More Info
Vincent Khoo
Principal Investigator
Nottingham University Hospitals NHS Trust - Nottingham City Hospital
Nottingham , NG5 1, United Kingdom More Info
Eliot Chadwick, MD
Principal Investigator

How clear is this clinincal trial information?

Study is for people with:

Prostate Cancer

Phase:

Phase 3

Estimated Enrollment:

1100

Study ID:

NCT04136353

Recruitment Status:

Recruiting

Sponsor:


University of Sydney

How clear is this clinincal trial information?

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