This is a multicenter, randomized, open label, phase III study comparing the efficacy and safety of apatulamide combined with concomitant prostate-bed salvage radiotherapy (SRT) and androgen deprivation therapy (ADT) versus concomitant prostate-bed SRT and ADT in high-risk postprostatectomy biochemically relapsed prostate cancer patients.

The purpose of the CARLHA-2 study is to determine if the combination of apalutamide with 6 months of LHRH agonists and radiotherapy results in an improvement of progression-free survival (PFS) in comparison to the combination of 6 months of LHRH agonists with radiotherapy in high-risk postprostatectomy biochemically relapsed prostate cancer patients.

Radical prostatectomy must have been done at least 6 months before inclusion and is not part of this study.

Patients after radical prostatectomy and biochemical relapse will be randomized in a 1:1 ratio to receive either 6 months of LHRH agonists + SRT or 6 months of LHRH agonists + SRT + 6 months of apalutamide.

The stratification variables include Gleason score, prostate-specific antigen (PSA), negative resection margins, extension to seminal vesicle(s), and PSA doubling time.

Inclusion Criteria:

1. Patients must have signed a written informed consent form prior to any trial specific procedures
2. Age ≥18 years old and ≤80 years old
3. Histologically confirmed diagnosis of prostate adenocarcinoma treated primarily with radical 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 pelvic 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 three consecutive 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 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 a calculated corrected creatinine clearance ≥60 mL/min according to the Cockcroft-Gault formula, creatinemia <2 ULN
11. Adequate hepatic function: total bilirubin ≤1.5 x ULN (unless documented Gilbert's syndrome), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN
12. Patients with QTc prolongation <500 ms, inclusion should considered after close benefit/risk assessment and cardiologist advice
13. Patients must be willing and able to comply with the protocol for the duration of the 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 other malignancy 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 that would interfere with enteral absorption
9. Uncontrolled hypertension (defined as systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
10. Clinically significant history of liver disease consistent with Child-Pugh class B or C
11. History of seizure or condition that may pre-dispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness ≤1 year prior to randomization; brain arteriovenous malformation or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
12. Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
13. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g pulmonary embolism, cerebrovascular accident including transient ischemic attacks) or clinically significant ventricular arrhythmias within 6 months prior to randomization
14. Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (e.g, heart failure, hypokalemia, or a family history of a long 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 or having been given an experimental drug within the 30 days before inclusion