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 trial specificprocedures
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 or pelvicnodal 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 at relapse >0.5 ng/mL or Gleason score >7 or tumor stage pT3b or resection margins R0 or PSAdoubling 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 the Cockcroft-Gaultformula, creatinemia <2 ULN
11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (unless documented Gilbert'ssyndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 xULN
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 of thestudy 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 conditions thatwould 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 B orC
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