| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hormone Naive Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hormone Naive Prostate Cancer |
|
| 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 | 10071119 |
| E.1.2 | Term | Hormone-dependent prostate cancer |
| 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 |
| The primary trial objective is to demonstrate that darolutamide produces prostate-specific antigen (PSA) response rates at 24 weeks (defined as ≥ 80% reduction compared to baseline) that are in the range of those achieved with 24 weeks of ADT. |
|
| E.2.2 | Secondary objectives of the trial |
• To document the effects of darolutamide compared to ADT in terms of patient-reported side effects of hormonal therapy, based on the HTR symptom scale of EORTC QLQ PR25 at 24 weeks;
• To document the effects of darolutamide compared to ADT in terms of patient-reported side effects of hormonal therapy, based on EORTC QLQ C30 and PR25 at 24 weeks;
• To document the effect of darolutamide on PSA complete response rate at 24 weeks (def as ≥ 90% red comp baseline);
• To document the effect of darolutamide on objective response rate at 24 weeks in patients with RECIST 1.1 measurable disease at baseline;
• To document the safety and tolerability of darolutamide vs. ADT in subjects who have not previously received hormone treatment for prostate cancer;
• To document the effects of darolutamide on androgen deprivations symptoms using the AMS questionnaires;
• To document the proportion of patients who opted to continue treatment with darol. beyond the 24 weeks evaluation time point. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Aged 18 years or older
• Histologically confirmed prostate cancer (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks
• M0 Patients or those presenting with a maximum of 4 confirmed metastatic lesions, including bone, extra-pelvic lymph nodes, and > 2 cm pelvic lymph nodes by imaging (contrast enhanced CT scans or MRI, Tc-99m BS according to local practice). Visceral metastases are excluded
• Asymptomatic for metastatic prostate cancer; urinary symptoms are allowed
• Baseline total testosterone ≥ 8 nmol/L or 230 ng/dL
• Two subsequent PSA values ≥ 2 ng/ml, done in the past 3 months (prior to enrollment) with a minimum of 2 weeks between the two, with the second being equal to or higher than the first
• WHO performance status (PS) of 0-1
• G8 score ≥ 14 for patients aged ≥ 70 years old
• A life expectancy of at least 12 months
• Able to swallow the study drug whole as a tablet
• Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 10^9/L; hemoglobin ≥ 10.0 g/dl; platelets ≥ 100 10^9/L)
• Adequate renal function: creatinine ≤ 1.5 x ULN
• Albumin > 25 g/L
• Adequate hepatic function:
- Bilirubin: total bilirubin ≤ 1.5 × upper limit of normal (ULN).
- AST and/or ALT ≤ 2.5 × ULN.
NOTE: patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry (except for serum creatinine) are acceptable.
• Normal 12-lead ECG as per local standard
• Patients of reproductive potential should use adequate birth control measures, during the study treatment period and for at least 3 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
|
| E.4 | Principal exclusion criteria |
• Previously or currently receiving hormonal therapy with intent to treat prostate cancer disease (surgical castration or other hormonal manipulation, e.g. LHRH agonists, LHRH antagonists, anti-androgens, oestrogens, 5α-reductase inhibitor). For patients that have received (neo)adjuvant ADT before radiotherapy, it should have been stopped for more than 1 year
• Prior use of investigational agents that block androgen synthesis or block androgen receptor
• Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g. saw palmetto)
• Has received systemic glucocorticoids within 24 weeks prior to enrollment or is expected to require systemic glucocorticoids during the study period, unless determined to be medically necessary by the investigator for other indications than prostate cancer.
• Radiation therapy for treatment of the primary tumor within 3 months prior to enrollment
• Use of an investigational agent within 4 weeks prior to enrollment is not allowed.
• Gastrointestinal disorder affecting absorption (e.g. gastrectomy, active peptic ulcer disease within 3 months prior to enrollment)
• Known hypersensitivity to the study treatment or any of its ingredients (refer to Investigator's brochure).
• Severe or uncontrolled concurrent disease, infection or co-morbidity including active viral hepatitis, known human immunodeficiency virus infection with detectable viral load (HIV) or chronic liver disease (Child Pugh C, see Appendix J)
• History of 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 from which the patient has been disease-free for a period of at least 5 years.
• Clinically significant cardiovascular disease including:
- Myocardial infarction within six months prior to randomization
- Uncontrolled angina within 3 months prior to randomization
- Coronary/peripheral artery bypass within 6 months prior to randomization
- Stroke within 6 months prior to randomization
- Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%
- History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
- History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
• Uncontrolled hypertension as indicated by a resting systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg at the screening visit |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the PSA response assessed at 24 weeks. PSA response is defined as a ≥ 80% decline in PSA measurement taken at week 24 relative to the measurement taken at baseline, in the darolutamide study arm. The ADT arm is used as an internal control. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The main key secondary endpoint is this study is the change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks compared to baseline in the darolutamide study arm.
Further key secondary endpoints are:
• Safety according to NCI-CTC version 4.0
• Objective response rate at 24 weeks in patients with RECIST 1.1 measurable disease at baseline
• PSA response at 24 weeks defined as a ≥ 90% decline in PSA compared to baseline.
• Overall survival rate at 24 weeks
• Cumulative incidence rate of patients who started further antineoplastic systemic therapy for progressive disease at 24 weeks
• The EORTC QLQ-C30 scales and the scales of the QLQ-PR25 other than the hormone-treatment related symptoms scale
• The AMS (Aging male symptoms)
• G8 baseline measurements in patients older than 70 years of age
• EQ-5D-5L to support the development of future hypotheses on HTA in a subsequent study
• Measurement of circulating levels of testosterone (free and total), DHT, SHBG, androstenedione, DHEA, LH, FSH, estradiol, prolactin
Long term outcomes at 2 year follow-up:
• Cumulative incidence rate of patients who started further antineoplastic systemic therapy for progressive disease
• Overall survival
• Percentage of patients who continued treatment with darolutamide beyond 24 weeks and their total treatment duration |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Egypt |
| Austria |
| France |
| Spain |
| Italy |
| Belgium |
| Norway |
|
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. At least thirty days after the end of the protocol treatment of the last patient and
2. Provided all patients have finished protocol specific procedures, not being otherwise part of the standard clinical practice. and
3. Provided the trial is mature for the analysis of the primary endpoint as defined in the protocol and
4. The database has been fully cleaned and frozen for this analysis. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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