E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adenocarcinoma of the prostate |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic prostate cancer |
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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) |
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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 compare the efficacy of ADT + darolutamide vs ADT + placebo in terms of radiographic progression-free survival (rPFS) in patients with castration-naïve de novo metastatic prostate cancer with vulnerable functional ability and not elected for docetaxel or other androgen receptor pathway inhibitors. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary objectives: -To assess the efficacy of ADT + darolutamide vs ADT + placebo in terms of: o Castration-resistant prostate cancer-free survival o Clinical progression-free survival (cPFS) o Overall survival
-To assess the safety profile of the ADT + darolutamide combination.
Other secondary objectives: -Time to worsening in prostate cancer-related urinary symptoms - Time to next symptomatic skeletal event - Prostate specific antigen (PSA) response - Prostate cancer-specific survival - To assess the effect of ADT + darolutamide on subsequent lines of therapy - To evaluate the evolution of quality of life and geriatric status in individuals during the treatment period. - To evaluate the impact of sarcopenia on survival and treatment response.
EXPLORATORY OBJECTIVES - To identify the oncogenic drivers of de novo metastatic prostate cancer.
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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 |
Same version as protocol (v2.0 - March 21th 2022 - section 9) BIOLOGICAL ANCILLARY/TRANSLATIONAL STUDIES
1. Samples Blood samples and tumour tissue will be collected across all trials in the PEACE 6 programme to address two current critical questions: (i) What are the oncogenic drivers of de novo metastatic prostate cancer? (ii) What is the underlying biology of oligometastatic prostate cancer? Analyses will include: Exome analysis Transcriptome analysis Immunohistochemistry Circulating tumour cells
2. Sarcopenia Additional data will be collected for consenting patients in order to answer the following secondary objectifve: what is the impact of sarcopenia on survival and treatment response? A complementary clinical evaluation will be performed by investigators and recorded in the eCRF at each timepoint, from Screening to End of treatment: - Abdominal circumference, weight and height and body mass index (BMI) - Maximum handgrip strength using a hand dynamometer |
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E.3 | Principal inclusion criteria |
1. Signed a written informed consent form prior to any trial specific procedures. Note: If the patient is physically unable to provide their written consent, a trusted person of their choice, independent of the Investigator or the Sponsor, can confirm the patients consent in writing. 2. Men with histologically or cytologically confirmed adenocarcinoma of the prostate. 3. Aged ≥18 years old at the time of signing informed consent. 4. De novo metastatic disease defined by clinical or radiographic evidence of metastases. Note: For patients with nodal metastases only, only patients with extra-pelvic enlarged lymph nodes (lymph nodes located above the iliac bifurcation) can be included if they have either: - At least one extra-pelvic lymph node ≥ 2 cm - At least one extra-pelvic lymph node ≥ 1 cm if the patients also have at least one pelvic lymph node ≥ 2 cm 5. Measurable disease or bone lesions that are evaluable according to PCWG3 criteria. 6. Ineligible for treatment with all of the following drugs: docetaxel, abiraterone, enzalutamide, apalutamide; AND meets at least one of the following frailty criteria: a. Activities of daily living (ADL) assessment (excluding urinary incontinence question) score 3 or 4/5; b. 4-Instrumental activities of daily living (4-IADL) assessment score 2 or 3/4; c. A Grade 3 event on the Cumulative Illness Score Rating-Geriatrics (CISR-G) questionnaire; d. Body mass index (BMI) ≤21 kg/m2 and/or >5% weight loss in the last 6 months; e. Timed up and go test (TUG) >14 sec. 7. Adequate bone marrow function: haemoglobin ≥80 g/L, white blood cells ≥3.0 x109/L and platelets ≥80 x109/L. 8. Adequate liver function: alanine aminotransferase (ALT) <2 x upper limit of normal (ULN) and bilirubin <1.5 x ULN, (or if bilirubin is between 1.5-2 x ULN, they must have a normal conjugated bilirubin). For patients with documented liver metastasis, ALT <5 x ULN is acceptable. 9. Adequate renal function: calculated creatinine clearance >30 ml/min (using the MDRD or CKD EPI method). 10. For sexually active men, agreement to use adequate contraception for the duration of trial participation and up to 2 weeks after completing study treatment. 11. Affiliated to the social security system or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials). 12. Willing and able to comply with the protocol for the duration of the trial including |
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E.4 | Principal exclusion criteria |
1. Three or more Grade 3, or any Grade 4 events on the CISR-G questionnaire. 2. Eastern Cooperative Oncology Group (ECOG) performance status score ≥3. 3. Hypertension not controlled by an anti-hypertensive treatment (systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5 minutes apart).4 4. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomisation, with the exception of hot flushes and erectile dysfunction. 5. Previous systemic treatment for prostate cancer, except less than 12 weeks of ADT and/or an old-generation AR inhibitor. 6. Severe or uncontrolled concurrent disease, infection or co-morbidity. 7. Known hypersensitivity to the study treatment or any of its ingredients. 8. Major surgery within 28 days before randomisation. 9. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV. 10. Prior malignancy ≤3 years before study enrolment. 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 localized cancer for which treatment has been completed ≥6 months before randomisation and from which the subject has been disease-free, or for which the risk of relapse is less than 30%, as well as early stage chronic lymphocytic leukaemia that does not require any specific treatment. 11. Inability to swallow oral medications. 12. Gastrointestinal disorder or procedure that can be expected to interfere significantly with the absorption of study treatment. 13. Known to have active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease at screening. 14. Treatment with any investigational product within 28 days before randomisation. 15. Concurrent participation in another clinical trial involving an investigational product (patients enrolled in non-experimental trials with no modification of the standard of care can be included). 16. Individual of full age deprived of liberty or placed under a legal protection measure (tutorship/curatorship/temporary guardianship). 17. Significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition that, in the opinion of the investigator, would preclude participation in this trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Radiographic progression-free survival, defined as time from randomisation to radiographic progression as assessed by the investigator according to PCWG3 criteria, or death, whichever occurs first. According to the PCWG3 recommendations, radiographic progression is defined as either the appearance of two or more new bone lesions on bone scan or a nodal or visceral progression according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). The date of radiographic progression will be the date of the first reported event meeting the above definition. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patient’s disease will be assessed at “baseline” (during the screening period) and then every 120 (±14) days after randomisation during the first 2 years and every 180 (±14) days thereafter, until documented radiographic progression, or death, whichever occurs first. |
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E.5.2 | Secondary end point(s) |
Key secondary endpoints: - Castration-resistant prostate cancer (CRPC)-free survival, defined as the time from randomisation to onset of CRPC according to PCWG3 criteria, or death, whichever occurs first. - Clinical progression-free survival, defined as time from randomisation to first occurrence of any one of the following: o Cancer pain deterioration (2-point deterioration from baseline according to the Brief Pain Inventory - Short Form [BPI-SF] questionnaire, or initiation of opioid therapy, or a ≥30% increase in opiate use), o Any deterioration of physical function measured using the 4-IADL assessment tool, o A deterioration in ECOG performance status of at least 2 points from baseline, o Death from any cause. - Overall survival, defined as the time from randomisation to the time of death from any cause. For subjects alive at the time of analysis, data will be censored on the last date the subject was known to be alive or lost to follow-up or withdraw consent. - Toxicity will be evaluated according to version 5 of the National Cancer Institut - Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0). Other secondary endpoints - Time to worsening in prostate cancer-related urinary symptoms, defined as an increase from baseline of greater or equal to 8 points in the urinary symptom scale/score (PRURI) measured using the prostate cancer module of the European organisation for research and treatment of cancer (EORTC) quality of life questionnaire (QLQ) (EORTC-QLQ-PR25). - Time to next symptomatic skeletal event, defined as the time from randomisation until first occurrence of one of the following: a symptomatic fracture, radiation or surgery to bone or a spinal cord compression (PCWG3 criteria). Note: The occurrence of these events will be determined by investigator evaluation. No systematic X-Ray will be performed. - Complete PSA response (defined as PSA ≤ 0.2 ng/ml) at 6 months. - Prostate cancer-specific survival, defined as the time from randomisation to the date of death due to prostate cancer (deaths due to other causes will be censored). - Time to deterioration for EORTC QLQ-PR25 symptom subscales, defined as the first decline in the HRQoL score from baseline equal to or greater than the minimally important difference (MID; a measure of clinical significance) defined as half the standard deviation of the baseline value for each subscale. - Time to first subsequent systemic anti-cancer therapy (SACT) defined as the time from randomisation to the date of initiation of any SACT for CRPC, following initiation of the study treatment. - Efficacy of subsequent SACT will be assessed according to rPFS, OS, and PFS after next line of treatment (PFS2); defined as the time from randomisation to second objective disease progression, or death from any cause, whichever first. - Health related quality of life will be evaluated using the EORTC-QLQ-C30, EORTC-QLQ-PR25 and BPI-SF questionnaires. - Geriatric status will be evaluated using the Geriatric Core Dataset (G-Code) assessment.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be asked to attend clinical visits to perform safety and efficacy assessments on Day 30 (±3 days), Day 60 (±3 days), Day 120 (±7 days), Day 180 (±7 days), Day 240 (±7 days) and then every 120 (±14) days for the first two years of treatment and every 180 (±14) days thereafter. Response to treatment will be assessed according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria by radiographic exams performed every 120 (±14) days after randomisation during the first 2 years and every 180 (±14) days thereafter. |
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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 | No |
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) | 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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
All patients (experimental and control arm) will receive Androgen deprivation therapy (ADT) |
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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 | 98 |
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 |
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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
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The end of trial is defined as last visit of the last subject(LVLS) |
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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 | 15 |
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 | 15 |