E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic hormone-sensitive prostate cancer (mHSPC) |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic prostate cancer responsive to hormone therapy which works by either stopping the body from making testosterone, or by stopping testosterone from reaching the cancer cells. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036909 |
E.1.2 | Term | Prostate cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine if darolutamide in addition to ADT is superior to placebo plus ADT by improving rPFS in participants with mHSPC. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate efficacy of darolutamide in addition to ADT compared to placebo plus ADT by improving OS, time to progress to CRPC, time to initiation of subsequent anti-cancer therapy, time to PSA progression, and undetectable PSA rates - To estimate the participant’s quality of life benefit of darolutamide in addition to ADT compared to placebo plus ADT by improving symptomatic time to pain progression - To assess the safety of darolutamide in addition to ADT compared to placebo plus ADT in participants with mHSPC |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Whole genome sequencing (WGS) will be offered to all participants. The WGS analysis will only be carried out in samples from those participants who have provided respective optional informed consent. Participants who do not wish to have their sample(s) analysed for WGS may still participate in the study. |
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E.3 | Principal inclusion criteria |
1. Written informed consent obtained. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 2. Males ≥18 years of age. 3. Histologically or cytologically confirmed adenocarcinoma of prostate. 4. Documented metastatic disease by conventional imaging method either by a positive 99mTc-phosphonate bone scan, or soft tissue or visceral metastases, either by contrastenhanced abdominal/pelvic/chest CT or MRI scan assessed by central review. Note: participants with a baseline "superscan" (bone scan showing a diffuse, intense, skeletal uptake of the tracer with absent renal and background activity) are considered ineligible. Note: Metastatic disease is defined as either malignant lesions in bone scan or measurable lymph nodes above the aortic bifurcation or soft tissue/visceral lesions according to RECIST version 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm, soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm. Regional lymph node metastases only (N1, below the aortic bifurcation) will not be considered as metastases eligible for the study. Only participants with non-regional lymph node metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases with or without bone disease (M1c), assessed according to National Comprehensive Cancer Network (NCCN) classification, will be eligible. 5. Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti–androgen, but not earlier than 12 weeks before randomization. For participants receiving LHRH agonists, treatment in combination with a first generation anti–androgen for at least 14 days prior to randomization is recommended. 6. First generation anti–androgen must be discontinued at least 1 day before study treatment start. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2. 8. Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, platelet count ≥100x109/L (participant must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening). 9. Screening values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 x ULN, total bilirubin ≤1.5 x ULN, creatinine ≤2.0 x ULN (for Canada: Screening values of serum alanine aminotransferase (ALT) and aspartate inotransferase (AST) =1.5 x ULN, total bilirubin =1.5 x ULN). 10. Sexually active male participants must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with study drug and for 4 weeks after the last does of the study treatment with study drug. 11. For Canada: At Screening; estimated glomerular filtration rate (eGFR) eGFR = 30 mL/min/1.73m2 (calculated by the CKD-EPI formula. |
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E.4 | Principal exclusion criteria |
1. Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the prostate. 2. Known brain/ leptomeningeal metastases Note: Brain CT/MRI scan should be performed only in case of symptoms. 3. Prior treatment with: - LHRH agonist/antagonists started >12 weeks before randomization starts except neoadjuvant and /or adjuvant therapy for a duration ≤ 24 months and completed ≥ 12 months prior to randomization - Second–generation androgen receptor (AR) inhibitors such as enzalutamide, darolutamide, apalutamide or other investigational AR inhibitors - Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as anti-cancer treatment for prostate cancer - Chemotherapy including docetaxel or immunotherapy for prostate cancer - Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days prior to randomization - radiopharmaceuticals - Any other anti-cancer treatment for prostate cancer, excluding local therapies and ADT 4. Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy) within 2 weeks before randomization. 5. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs. 6. Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast agent(s). 7. Any prior malignancy (other than adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) within 5 years prior to randomization. 8. An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] hepatitis B virus [HBV] DNA or defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), known human immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment. Note: No testing for Hepatitis B and/or Hepatitis C is required unless mandated by local authority. No HIV testing is required unless mandated by local authority. 9. Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV). 10. Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg despite medical management. 11. A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly with absorption of study drug. 12. Previous (within 28 days before the start of study drug or 5 half–lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s). 13. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the participant and/or his/her compliance with study procedures or may interfere with the participant's participation in the study or evaluation of the study results. 14. Inability to swallow oral medications. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Radiological progression-free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of randomization to the date of first documentation of radiological progressive disease or death due to any cause, whichever occurs first, assessed 36 months after first patient randomized. |
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E.5.2 | Secondary end point(s) |
1) Overall survival (OS) 2) Time to castration–resistant prostate cancer (CRPC) 3) Time to initiation of subsequent anti-cancer therapy 4) Time to PSA progression 5) Percentage of participants with detectable PSA values (≥0.2 ng/mL) at baseline which become undetectable (<0.2 ng/mL) 6) Time to pain progression 7) Number of participants with treatment emergent adverse events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Time from the date of randomization to the date of death from any cause at 3 years 2) From the date of randomization to the date of first castration resistant event (radiological progression, PSA progression or symptomatic skeletal events, whichever occurs first), assessed at 3 years. 3) From the date of randomization to initiation of first subsequent anti-cancer therapy for prostate cancer, assessed at 3 years. 4) From the date of randomization to the date of first PSA progression , assessed at 3 years. 5) Baseline and during study treatment. 6) From the date of randomization to pain progression, assessed at 3 years. 7) After the first dose of study drug until 30 days (+7 days) after the last treatment with darolutamide/placebo assessed at 3 years.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Chile |
China |
India |
New Zealand |
Peru |
South Africa |
Taiwan |
United States |
Latvia |
Lithuania |
Spain |
Russian Federation |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |