Study Evaluating the Efficacy and Safety of Darolutamide and Stereotactic Dose Escalated Radiotherapy in Patients With Localized Prostate Cancer and High-risk Features of Relapse

Inclusion criteria

• Signed a written informed consent form prior to any trial specific procedures

Note: In case of physical incapacitation, a trusted representative of their choice, which is not the investigator or sponsor, can sign on the behalf of the patients

• Men, 18 years ≤ Age ≤ 80 years
• ECOG performance status of 0 or 1
• No significant co-morbidities that might prevent long-term follow-up
• Histologically confirmed adenocarcinoma of the prostate
• Meet at least 2 of the following criteria from NCCN classification:

• Gleason score ≥8
• T3 or T4 disease (T3 defined by MRI is acceptable)
• Prostate-specific antigen ≥20 ng/mL
• Prostate size on MRI <100 cc
• Absolute neutrophil count ≥ 1.5 x 10⁹/L
• Platelet count ≥100 x 10⁹/L
• Haemoglobin ≥90 g/L (in absence of red blood cell transfusion within 4 weeks prior to randomization)
• Hepatic function: serum alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≤2.5 x upper limit of normal (ULN), total bilirubin ≤1.5 x ULN
• Creatinine ≤2.0 x ULN
• Sexually active patients must agree to use an effective contraceptive method while on treatment and for 1 week after the final dose of investigational product
• Patient must be affiliated to a Social Security System or in possession of equivalent private health insurance (according to local regulations for participation in clinical trials)
• Patient must be willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up

Exclusion criteria

• Clinically or radiologically detectable metastasis, including no evidence of pelvic lymph node metastasis on next generation imaging (PSMA PET/CT), nor enlarged pelvic lymph nodes (≥1 cm in small diameter) on MRI Note: Patients with infra-centimetric nodal disease (<1 cm in small diameter) on conventional imaging and equivocal hyperfixation on next generation imaging may be included
• Recent history of TURP or prostate enucleation (less than 6 months) Note: patients with severe obstructive symptoms (defined as International Prostate Symptom Score (IPSS) ≥20) should be carefully evaluated to rule out the need for TURP/Prostate enucleation
• Prior treatment for prostate cancer, including prostatectomy, except lymph node dissection (patients with PN- disease only can be accrued) or ADT (started more than 6 weeks before randomization)
• Patient with other known concurrent severe and/or uncontrolled concurrent medical disease or infection (such as active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease) or co-morbidity, which could compromise participation in the study
• Cardiac disease such as uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg; 3 consecutive measures taken 5 minutes apart), stroke, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within one year, coronary/peripheral artery bypass graft, LVEF > grade 2
• Uncontrolled diabetes mellitus
• Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment)
• Gastrointestinal disorder or procedure, which expects to interfere significantly with absorption of study treatment. Severe GI disorders precluding pelvic irradiation
• Known severely impaired lung function (spirometry and DLCO 70% or less of normal and O2 saturation of 88% or less at rest on room air)
• Other prior malignancy within the last 3 years, except basal cell skin cancer
• Known hypersensitivity to the study treatment or any of its ingredients.
• Physical or psychological condition or any condition that in the opinion of the investigator would impair the patients' ability to comply with the study procedures
• Previous treatment for prostate cancer (surgery or radiotherapy) or previous pelvic irradiation that would make prostate/pelvis radiotherapy impossible
• Concomitant prohibited treatment. Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5. A one-week washout period is necessary for patients who are already on these treatments
• Prior treatment with second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor
• Use of oestrogens or 5-α reductase inhibitors or AR inhibitors
• Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomization
• Prior chemotherapy or immunotherapy for prostate cancer
• Major surgery within 28 days before randomization
• Participation in another therapeutic trial within 30 days prior to inclusion
• Persons deprived of their liberty or under protective custody or guardianship
• Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons