Clinically localised prostate cancer defined as very high risk, or with very high risk features. MedDRA version: 20.0 Level: PT Classification code 10060862 Term: Prostate cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Darolutamide
Product Code: BAY 1841788 (darolutamide, ODM-201)
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: DAROLUTAMIDE
Other descriptive name: BAY 1841788 (darolutamide
Sponsors
Cancer Trials Ireland
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Men aged 18 years and older, with pathological diagnosis of adenocarcinoma of the prostate. 2. 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) * Screening PSA levels are those measured within 240 days prior to randomisation. 3. Adequate bone marrow function: Haemoglobin = 100g/L, white cell count (WCC) = 4.0x10^9/L, absolute neutrophil count (ANC) = 1.5x10^9/L and platelets > 100 x 10^9/L 4. Adequate liver function: alanine aminotransferase (ALT) 30 mL/min (Cockroft-Gault) 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. 7. Study treatment both planned and able to start within 7 days after randomisation 8. Willing to complete health-related quality of life (HRQL) questionnaires UNLESS is unable to complete because of literacy or limited vision 9. Willing and able to comply with all study requirements, including standard of care treatment such as EBRT, timing and/or nature of required assessments 10. Signed, written informed consent Additional: Conventional imaging must be used to confirm eligibility and disease progression, PSMA PET alone is not considered enough. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: 11. Prostate cancer with predominant non-adenocarcinoma features(sarcomatoid/spindle cell/neuroendocrine small cell/squamous cell components/other non-adenocarcinoma) 12. 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). 13. Evidence of metastatic disease. Minimum imaging requirements to exclude metastatic disease are defined in the trial protocol. • If endocrine therapy (ET)had not started,imaging must be within 60 days prior to randomisation. • If ET has been started,radiographic imaging (CT/MRI/CXR)must have been performed no more than 60 days prior to starting ET&no more than 30 days after starting ET &prior to randomisation. Refer to protocol for further detail. 14. PSA >100 ng/mL at any time. 15. Any prior use of new generation potent AR inhibition(abiraterone,enzalutamide,apalutamide,darolutamide or similar agents). 16. 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&if used,it must be stopped before starting study treatment with darolutamide/placebo. 17. Bilateral orchidectomy 18. Prior pelvic brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields that would preclude the required RT 19. 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,coronary artery bypass graft.Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. 20. Known gastrointestinal disease/procedure that could interfere with the oral absorption or tolerance of darolutamide,including difficulty swallowing tablets 21. 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 &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&other adequately treated in-situ neoplasms are not considered malignancies for the purposes of eligibility assessment. 22. Concurrent illness,including severe infection that might jeopardise the ability of the participant to undergo the procedures outlined in the 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) 23. Presence of any psychological,familial,sociological or geographical condition potentially hampering compliance with the study protocol &follow-up schedule,including alcohol dependence or drug abuse 24. Pa
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objective: 1. Metastasis-free survival (MFS) (metastasis or death from any cause);Secondary Objective: Secondary objectives: 2. Overall survival (OS) (death from any cause) 3. Prostate cancer-specific survival 4. PSA-progression free survival 5. Time to subsequent hormonal therapy (restart or change to treat recurrence/progression) 6. Time to castration-resistance (PCWG3 criteria) 7. Frequency and severity of adverse events (CTCAE v5.0, RTOG/EORTC acute/late radiation morbidity criteria) 8. Health related quality of life (EORTC QLQ-C30, QLQ-PR25, EQ-5D-5L) 9. Fear of cancer recurrence (FCR) (FCRI) Tertiary objectives: 10. Incremental cost-effectiveness Also to: 11. Identify biomarkers that are prognostic, and/or predictive of response to treatment, safety and resistance to study treatment (associations of biomarkers with clinical outcomes).;Primary end point(s): Metastasis-free survival (MFS). ;Timepoint(s) of evaluation of this end point: 1,100 participants followed until 130 MFS events are recorded (e.g. given a 3 year accrual period plus at least 4 years of follow-up, and an 85% 5-year MFS in control arm). An unblinded interim analysis on MFS is planned once 67% of the 130 required events have been recorded. Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial Statistical Analysis Plan. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall survival - Prostate cancer-specific survival - PSA-progression free survival - Time to subsequent hormonal therapy - Time to castration-resistance - Frequency and severity of adverse events - Health-related quality of life - Fear of cancer recurrence - Incremental cost-effectiveness - Prognostic/predictive biomarkers;Timepoint(s) of evaluation of this end point: 1,100 participants followed until 130 MFS events are recorded (e.g. given a 3 year accrual period plus at least 4 years of follow-up, and an 85% 5-year MFS in control arm). An unblinded interim analysis on MFS is planned once 67% of the 130 required events have been recorded. Final analysis will be performed after the study has been completed, the data cleaned, and the database closed out, according to the trial Statistical Analysis Plan. | — |
Countries
Australia, Canada, Ireland, New Zealand, United Kingdom, United States
Contacts
Public ContactHead of Clinical Operations
Cancer Trials Ireland
Outcome results
None listed