Combined Apalutamide, Radiotherapy, and LHRH Agonist in Prostate Cancer Patients After Prostatectomy

Inclusion Criteria:

1. Patients must have signed a written informed consent form prior to any trialspecific procedures

2. Age ≥18 years old and ≤80 years old

3. Histologically confirmed diagnosis of prostate adenocarcinoma treated primarily withradical prostatectomy

4. Tumor stage pT2, pT3 or pT4* (*only in case of bladder neck involvement)

5. Patients should have no clinical and radiological signs (18FCH-PET CT-scan or 68Ga-PSMA-PET CT-scan) of metastatic disease. Patients with a local relapse orpelvic nodal relapse (N1) detected on PET CT-scan can be randomized

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1

7. PSA ≥0.2 ng/mL at the time of randomization with an elevation of PSA over threeconsecutive assays. PSA increases over a 1-month interval minimum

8. At least 3 months between radical prostatectomy and randomization.

9. High-risk features as defined by at least one of these characteristics: PSA atrelapse >0.5 ng/mL or Gleason score >7 or tumor stage pT3b or resection margins R0or PSA doubling time ≤6 months or pelvic lymph node relapse (N1, ≤5 lymph nodes)

10. Adequate renal function: serum creatinine <1.5 x upper limit of normal (ULN) or acalculated corrected creatinine clearance ≥60 mL/min according to theCockcroft-Gault formula, creatinemia <2 ULN

11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (unless documented Gilbert'ssyndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN

12. Patients with QTc prolongation <500 ms, inclusion should considered after closebenefit/risk assessment and cardiologist advice

13. Patients must be willing and able to comply with the protocol for the duration ofthe study including undergoing treatment and scheduled visits and examinations

14. Patients must be affiliated to the Social Security System

Exclusion Criteria:

1. Previous treatment with hormone therapy for prostate cancer

2. Histology other than adenocarcinoma

3. Surgical or chemical castration

4. Other malignancy except adequately treated basal cell carcinoma of the skin or othermalignancy from which the patient has been cured for at least 5 years

5. Previous pelvic radiotherapy

6. More than 5 (>5) pelvic lymph node relapses

7. Paraaortic, thoracic or supaclavicular nodal relapse (M1a)

8. History of Inflammatory bowel disease or any malabsorption syndrome or conditionsthat would interfere with enteral absorption

9. Uncontrolled hypertension (defined as systolic blood pressure (BP) ≥140 mmHg ordiastolic BP ≥90 mmHg). Patients with a history of hypertension are allowed providedblood pressure is controlled by anti-hypertensive treatment

10. Clinically significant history of liver disease consistent with Child-Pugh class Bor C

11. History of seizure or condition that may pre-dispose to seizure (including, but notlimited to prior stroke, transient ischemic attack or loss of consciousness ≤1 yearprior to randomization; brain arteriovenous malformation or intracranial masses suchas schwannomas and meningiomas that are causing edema or mass effect)

12. Medications known to lower the seizure threshold must be discontinued or substitutedat least 4 weeks prior to study entry

13. Severe or unstable angina, myocardial infarction, symptomatic congestive heartfailure, arterial or venous thromboembolic events (e.g pulmonary embolism,cerebrovascular accident including transient ischemic attacks) or clinicallysignificant ventricular arrhythmias within 6 months prior to randomization

14. Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointesventricular arrhythmias (e.g, heart failure, hypokalemia, or a family history of along QT syndrome), a QT or corrected QT (QTc) interval >500 ms at baseline

15. Medications known to prolong QTc

16. Known hypersensitivity to apalutamide or to any of its components

17. Galactosemia, Glucose-galactose malabsorption or lactase deficiency

18. Inability or willingness to swallow oral medication

19. Individual deprived of liberty or placed under the authority of a tutor

20. Patients already included in another therapeutic trial with an experimental drug orhaving been given an experimental drug within the 30 days before inclusion