E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic hormone-sensitive prostate cancer (mHSPC) |
|
E.1.1.1 | Medical condition in easily understood language |
Prostate cancer which does respond to hormonal treatment |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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) |
|
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 demonstrate the superiority in overall survival of darolutamide in addition to standard androgen deprivation therapy (ADT) and docetaxel
over placebo in addition to standard ADT and docetaxel |
|
E.2.2 | Secondary objectives of the trial |
• Time to castration-resistant prostate cancer
• Time to initiation of subsequent antineoplastic therapy
• Symptomatic skeletal event free survival (SSE-FS)
• Time to first symptomatic skeletal event (SSE)
• Time to initiation of opioid use for ≥7 consecutive days
• Time to pain progression
• Time to worsening of physical symptoms of disease based on Functional assessment of cancer therapy / National Comprehensive Cancer Network prostate cancer symptom index 17 (NCCN-FACT FPSI-17)
• Safety |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet the following criteria at the time of Screening:
1. Written informed consent.
2. Males ≥18 years of age.
3. Histologically or cytologically confirmed adenocarcinoma of prostate.
4. Metastatic disease documented either by a positive bone scan, or for soft tissue or visceral metastases, either by contrast-enhanced abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed by Investigator and confirmed by central radiology review. 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 Response Evaluation Criteria In Solid Tumors (RECIST) 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.
• Subjects with regional lymph node metastases only (N1, below the aortic bifurcation) will not be eligible for the study. Only subjects with non-regional lymph node metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases with or without bone disease (M1c) will be eligible.
5. Subjects must be candidates for ADT and docetaxel therapy per Investigator’s judgment.
6. Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but no longer than 12 weeks before randomization. For subjects receiving LHRH agonists, treatment in combination with a first generation anti-androgen for at least 4 weeks prior to randomization is recommended. First generation anti-androgen has to be stopped prior to randomization.
7. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
8. Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, platelet count ≥100x109/L (subject 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/or aspartate transaminase (AST) ≤1.5 x upper limit of normal (ULN), total bilirubin ≤ULN, creatinine ≤2.0 x ULN.
10. Sexually active male subjects 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 darolutamide /placebo and for 3 months after treatment with darolutamide/placebo and 6 months after treatment with docetaxel. |
|
E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria at the time of Screening will be excluded:
1. Prior treatment with:
• LHRH agonist/antagonists started more than 12 weeks before randomization
• Second-generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-509, darolutamide, other investigational AR inhibitors
• Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer
• Chemotherapy or immunotherapy for prostate cancer prior to randomization
2. Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) within 2 weeks before randomization.
3. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
4. Contraindication to both CT and MRI contrast agent.
5. 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).
6. Uncontrolled hypertension as indicated by a resting systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg despite medical management.
7. Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed ≥5 years before randomization and from which the subject has been disease-free.
8. A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug.
9. An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need of treatment.
10. 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).
11. Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject’s participation in the study or evaluation of the study results.
12. Inability to swallow oral medications.
13. Close affiliation with the investigational site (e.g., a close relative of the Investigator, dependent person [e.g., employee or student of the investigational site]).
14. Previous assignment to treatment in this study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival, defined as the time (in days) from date of randomization until death from any cause. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be performed when approximately 509 deaths occur in the 2 treatment arms combined. The expected study duration for 509 deaths is approximately 70 months. |
|
E.5.2 | Secondary end point(s) |
• Time to castration-resistant prostate cancer
• Time to initiation of subsequent antineoplastic therapy
• Symptomatic skeletal event free survival (SSE-FS)
• Time to first symptomatic skeletal event (SSE)
• Time to initiation of opioid use for ≥7 consecutive days
• Time to pain progression
• Time to worsening of physical symptoms of disease based on NCCN-FACT FPSI-17
• Safety |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Time to PSA progression with serum testosterone being at castrate level <0.50 ng/mL,or the time to progression by soft tissue lesions or time to progression by bone lesions
•Time from randomization to initiation of first subsequent antineoplastic therapy for prostate cancer
•Time from randomization to the first occurrence of SSE or death from any cause
•Time from randomization to the first occurrence of SSE
•Time from date of randomization to the date of first opiate use for ≥7 consecutive days
•Interval from randomization to the first date a subject experiences a pain progression
•Interval from randomization to the first date a subject experiences an increase in physical symptoms based on the NCCN FACT FPSI 17 questionnaire.
•Refer to protocol section 10.3.3 for safety variables |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 137 |
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 |
China |
Israel |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Taiwan |
United States |
Belgium |
Czechia |
Finland |
France |
Germany |
Italy |
Poland |
Sweden |
United Kingdom |
Bulgaria |
Netherlands |
Spain |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
LVLS
The study will end when all subjects on darolutamide treatment have transitioned into a separate program to continue receiving darolutamide (see protocol Section 8.2) or have discontinued the study for any other reason, and all subjects on placebo have discontinued treatment.
Until transition to the separate program, subjects on darolutamide treatment will continue to follow all the protocol required procedures and visits in the current protocol. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 25 |