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

1. 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

2. 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

3. 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)

4. 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

5. 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

6. Uncontrolled diabetes mellitus

7. Current active hepatic or biliary disease (with exception of subjects with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment)

8. Gastrointestinal disorder or procedure, which expects to interfere significantly with absorption of study treatment. Severe GI disorders precluding pelvic irradiation

9. 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)

10. Other prior malignancy within the last 3 years, except basal cell skin cancer

11. Known hypersensitivity to the study treatment or any of its ingredients.

12. 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

13. Previous treatment for prostate cancer (surgery or radiotherapy) or previous pelvic irradiation that would make prostate/pelvis radiotherapy impossible

14. 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

15. Prior treatment with second generation androgen receptor (AR) inhibitors, other investigational AR inhibitors, or CYP17 enzyme inhibitor

16. Use of oestrogens or 5-α reductase inhibitors or AR inhibitors

17. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or baseline before randomization

18. Prior chemotherapy or immunotherapy for prostate cancer

19. Major surgery within 28 days before randomization

20. Participation in another therapeutic trial within 30 days prior to inclusion

21. Persons deprived of their liberty or under protective custody or guardianship

22. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons

What this study is about