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

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

• Patients must have signed a written informed consent form prior to any trial specific procedures
• Age ≥18 years old and ≤80 years old
• Histologically confirmed diagnosis of prostate adenocarcinoma treated primarily with radical prostatectomy
• Tumor stage pT2, pT3 or pT4* (*only in case of bladder neck involvement)
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1
• 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
• At least 3 months between radical prostatectomy and randomization.
• 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)
• 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
• 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
• Patients with QTc prolongation <500 ms, inclusion should considered after close benefit/risk assessment and cardiologist advice
• 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
• Patients must be affiliated to the Social Security System

Exclusion criteria

• Previous treatment with hormone therapy for prostate cancer
• Histology other than adenocarcinoma
• Surgical or chemical castration
• 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
• Previous pelvic radiotherapy
• More than 5 (>5) pelvic lymph node relapses
• Paraaortic, thoracic or supaclavicular nodal relapse (M1a)
• History of Inflammatory bowel disease or any malabsorption syndrome or conditions that would interfere with enteral absorption
• 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
• Clinically significant history of liver disease consistent with Child-Pugh class B or C
• 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)
• Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
• 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
• 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
• Medications known to prolong QTc
• Known hypersensitivity to apalutamide or to any of its components
• Galactosemia, Glucose-galactose malabsorption or lactase deficiency
• Inability or willingness to swallow oral medication
• Individual deprived of liberty or placed under the authority of a tutor
• Patients already included in another therapeutic trial with an experimental drug or having been given an experimental drug within the 30 days before inclusion