Adjuvant Apalutamide in Subjects With High-risk Localized or Locally Advanced Prostate Cancer After Radical Prostatectomy

Inclusion criteria

• Signed informed consent form (ICF).
• Men ≥ 18 years of age.
• Patients with histologically confirmed adenocarcinoma of the prostate after radical prostatectomy.
• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1.
• Exclusion of metastatic disease by computed tomography (CT)-scan of abdomen (magnetic resonance imaging (MRI) of abdomen is possible) and bone scan prior to study inclusion. A PSMA PET-CT/MRI is possible. In this case it has to be done with a diagnostic CT/MRI with contrast media and not with a low dose CT-scan only. In case PSMA-PET imaging has been done, a bone scan can be omitted. CT/MRI, and bone-scan imaging or PSMA PET-CT/MRI administered ≤12 weeks before RPE may be used for screening.
• Patients after radical prostatectomy must meet the d'Amico criteria for high risk of disease recurrence: i.e. one of the following after RPE: 1) Gleason score ≥8, any T-stage, any initial PSA (iPSA) or 2) Gleason score 6 or 7, any iPSA and ≥pT3c or 3) iPSA >20 ng/ml, any Gleason score, any T-stage.
• Patients have to have recovered from radical prostatectomy within four weeks to be able to take part in the study.
• PSA-value must have declined below 0.2 ng/ml prior to randomization
• Adequate hematologic, hepatic, and renal function:

Hematologic

• Haemoglobin ≥9.0 g/dL independent of transfusions
• Neutrophils ≥1.5 Ths./µL

Hepatic:

• Total bilirubin ≤1.5X upper limit of normal (ULN) [except for subjects with documented Gilbert's disease in which case total bilirubin not to exceed 10X ULN]
• Alanine (ALT) and aspartate (AST) aminotransferase ≤2.5X ULN

Renal:

• Serum creatinine <1.5X ULN or calculated creatinine clearance ≥50 mL/min
• Serum potassium ≥3.5 mM
• Serum albumin ≥ 3.0 g/dL.
• Ability to swallow study medication tablets.
• In case of apalutamide treatment: Agrees to use a condom and another highly effective method of birth control if he is having sex with a woman of childbearing potential or to use a condom if he is having sex with a woman who is pregnant

Exclusion criteria

• Any chronic medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone q.d.
• Prior cytotoxic chemotherapy or biologic therapy for the treatment of prostate Cancer.
• Prior or current treatment of prostate cancer with apalutamide, enzalutamide, darolutamide, or other investigational agents targeting the androgen receptor.
• Prior therapy with Sipuleucel-T or other vaccination or immunogenic therapy for the treatment of prostate Cancer.
• Prior treatment with abiraterone acetate or other androgen synthesis inhibitors (e. g. ketoconazole, TAK700, TOK001).
• Use of 5-α reductase inhibitors (eg, dutasteride, finasteride) ≤4 weeks prior to randomization.
• Prior surgical castration or medical castration using LHRH-Agonists or GnRH-Antagonists.
• Prior or current radiation or radionuclide (including radium-223 dichloride) therapy for treatment of prostate cancer (adjuvant radiation of the prostate bed without involvement of the regional lymph node template as by standard of care in case of positive surgical margins (R1) is allowed).
• Prior or current systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1.
• Any lymph node or distant metastasis.
• History of seizure or condition that may predispose 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).
• Current or prior treatment with anti-epileptic medications for the treatment of seizures.
• Management of cardiovascular risk factors, such as hypertension, diabetes or dyslipidaemia should be optimised as per standard of care before treatment with apalutamide will be initiated

13.1. Uncontrolled hypertension (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg. For patients with relevant comorbidities (e.g. diabetes) systolic BP ≥130 mmHg or diastolic BP ≥80 mmHg). Patients with a history of hypertension are allowed provided that blood pressure is controlled by anti-hypertensive Treatment

13.2. Patients with uncontrolled diabetes defined as HbA1c ≥7.5%

13.3. Patients with a dyslipidemia defined as LDL cholesterol >100 mg/dl. For patients with a dyslipidemia defined as LDL cholesterol >100 mg/dl and SCORE-value of 1-5%: In case of a SCORE-value of <1% a LDL cholesterol level of up to 115 mg/dl is acceptable. In case of increased LDL cholesterol above these values a statin-therapy can be initiated and a rescreening within 4 weeks is possible

13.4. Cardiovascular risk assessment via an appropriate score (e.g. the SCORE-Chart for the European high/low risk score from the European Society of Cardiology) and ≥ borderline risk i.e. 10% of developing cardiovascular events within 10 years without prior established cardiovascular disease

• Active or symptomatic viral hepatitis or chronic liver disease or HIV.
• History of pituitary or adrenal dysfunction.
• Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of <50% at baseline.
• Any condition that requires treatment with digoxin, digitoxin, and other digitalis drugs.
• Long QT-Syndrome.
• Atrial Fibrillation, or other cardiac arrhythmia requiring therapy.
• Other malignancy with a ≥30% probability of recurrence within 24 months, except non-melanoma skin Cancer.
• Any condition, which, in the opinion of the investigator, would preclude participation in this trial.
• Gastrointestinal conditions affecting Absorption.
• Hypersensitivity to the active substance, or to any of the excipients of the study medication.
• Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator's opinion, compromises the patient's ability to understand the patient information, to give informed consent or to comply with the study protocol.
• Participation in another interventional clinical trial during this trial or within 4 weeks before entry into this trial. There may be exceptions at the discretion of the (coordinating) investigator.