A MULTINATIONAL, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE III EFFICACY AND SAFETY STUDY OF DAROLUTAMIDE (ODM-201) IN MEN WITH HIGH-RISK NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Phase 1

Conditions: MedDRA version: 21.1Level: PTClassification code 10062904Term: Hormone-refractory prostate cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
High-risk, non-metastatic castration-resistant prostate cancer (MedDRA: hormonerefractory prostate cancer)
MedDRA version: 21.1Level: LLTClassification code 10066489Term: Progression of prostate cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2013-003820-36-LV

Lead Sponsor: Bayer AG

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Male

Target Recruitment: 1500

Inclusion Criteria

1. Written informed consent (IC) obtained.
2. Males aged = 18 years.
3. Histologically or cytologically confirmed adenocarcinoma of prostate without neuroendocrine differentiation or small cell features.
4. CRPC is defined as 3 rising PSA levels after the nadir taken at least 1 week apart during ADT. If the patient has a history of antiandrogen use, the most recent PSA value must be obtained at least 4 weeks after antiandrogen withdrawal. See Section 6.1.1 of the Protocol for further details.
5. Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or antagonist therapy or after bilateral orchiectomy. Patients who have not undergone bilateral orchiectomy must continue GnRH therapy during the study.
6. PSADT of = 10 months and PSA > 2 ng/ml at screening.See Section 6.1.1 of the Protocol for further details.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
8. Blood counts at screening: haemoglobin = 9.0 g/dl, absolute neutrophil count = 1500/µl (1.5x10^9/l), platelet count = 100,000/µl (100x10^9/l ) (patient must not have received any growth factor or blood transfusion within 7 days of the haematology laboratory obtained at screening).
9. Screening values of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) = 2.5 x upper limit of normal (ULN), total bilirubin = 1.5 x ULN (except patients with a diagnosis of Gilbert’s disease), creatinine = 2.0 x ULN.
10. Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier method and refrain from sperm donation during the study treatment and for 3 months after the end of the study treatment.

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 300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1200

Exclusion Criteria

1. History of metastatic disease at any time or presence of detectable metastases by blinded central reading within 42 days prior to start of study treatment. Presence of pelvic lymph nodes < 2 cm in short axis below the aortic bifurcation is allowed. See Section 6.1.1 of the Protocol for further details.
2. Symptomatic local-regional disease that requires medical intervention including moderate/severe urinary obstruction or hydronephrosis due to prostate cancer.
3. Acute toxicities of prior treatments and procedures not resolved to grade <=1 or baseline before randomisation.
4. Prior treatment with: second generation AR inhibitors such as enzalutamide, ARN-509, darolutamide, other investigational AR inhibitors,
CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or
oral ketoconazole longer than for 28 days.
5. Use of estrogens or 5-a reductase inhibitors (finasteride, dutasteride) within 28 days before randomisation and AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) at least 28 days before screening.
6. Prior chemotherapy or immunotherapy for prostate cancer, except adjuvant/neoadjuvant treatment completed > 2 years before randomisation.
7. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 28 days before randomisation.
8. Radiation therapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) within 12 weeks before randomisation.
9. Severe or uncontrolled concurrent disease, infection or co-morbidity that, in the opinion of the investigator, would make the patient inappropriate for enrolment.
10. Treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent skeletal-related events within 12 weeks before randomisation. Patients receiving osteoclast-targeted therapy to prevent bone loss at a dose and schedule indicated for osteoporosis may continue treatment at the same dose and schedule.
11. Known hypersensitivity to the study treatment or any of its ingredients.
12. Major surgery within 28 days before randomisation.
13. 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.
14. Uncontrolled hypertension as indicated by a systolic BP >=160 mmHg or diastolic BP >=100 mmHg at screening.
15. 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 ago and from which the patient has been disease-free.
16. Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study treatment.
17. Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease.
18. Treatment with any investigational drug within 28 days before randomisation.
19. Any condition that in the opinion of the investigator would impair the patients’ ability to comply with the study procedures.
20. Unable to swallow study medications and comply with study requirements.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to demonstrate the superiority of darolutamide vs. placebo in metastasis free survival (MFS) in patients with high-risk nmCRPC;Secondary Objective: The secondary objectives of this study are to demonstrate the benefit of darolutamide for:<br>Overal survival (OS), time to first symptomatic skeletal related event (SSE), time to initiation of first cytotoxic chemotherapy for prostate cancer, time to pain progression and to characterise the safety and tolerability of darolutamide;Primary end point(s): The primary efficacy variable is metastasis free survival (MFS), defined as time between randomisation and evidence of metastasis or death from any cause, whichever occurs first;Timepoint(s) of evaluation of this end point: Will be evaluated at about 385 events

Secondary Outcome Measures

Name	Time	Method

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