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

Study Overview
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Brief Summary
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The primary objective of this trial is to determine if adjuvant apalutamide in prostate cancer patients at high risk of developing subsequent metastatic disease results in prolonged biochemically recurrence-free survival after radical prostatectomy (RPE) in comparison to standard of care (SOC).

Official Title
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A Randomized, Open-label, Phase 2 Study of Adjuvant Apalutamide or Standard of Care in Subjects With High-risk, Localized or Locally Advanced Prostate Cancer After Radical Prostatectomy

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Other: Standard of care
* Drug: Apalutamide 60Mg Tab


Participation Criteria
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Eligibility Criteria
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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 CT-scan of thorax and abdomen (MRI of abdomen is possible) and bone scan prior to radical prostatectomy. 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 ≥pT2c 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standard of care<br>Observation only or An optional adjuvant radiation of the prostate bed in case of positive surgical margin | Other: Standard of care<br>* Observation only or An optional adjuvant radiation of the prostate bed in case of positive surgical margin<br>|
| Experimental: Apalutamide<br>30 cycles apalutamide 240 mg (4 x 60 mg) once daily on days 1-28 of a 28-day cycle in addition to standard of care | Other: Standard of care<br>* Observation only or An optional adjuvant radiation of the prostate bed in case of positive surgical margin<br>Drug: Apalutamide 60Mg Tab<br>* (4 x 60 mg) once daily on days 1-28 of a 28-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS). | This endpoint is defined as time interval from randomization until BCR (irrespective of the PSADT), metastases, or death from any cause, whichever occurs first. BCR is defined as a PSA ≥ 0.2 ng/ml that has risen on at least two separate occasions at least four weeks ± 3 days apart and measured by the central PSA-lab. The time of BCR is then backdated to the time of the first increased PSA measurement. Metastatic disease will be defined as the presence of bone metastases visualized on bone scan prostate cancer working group 3 (PCWG3)-criteria; and/or visceral (e.g. liver, lung, brain) or extra-pelvic nodal metastases visualized on CT scan (or MRI scan) (RECIST 1.1-criteria). Evaluations will be performed every 6 months once BCR occurred or sooner if clinically indicated. For a patient with none of these events before the end of follow-up, observation of PFS will be censored at the date of his date of last contact. | From date of randomization until the date of first documented progression (BCR or metastases) or date of death from any cause, whichever came first, assessed up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA doubling time (PSADT) | In case of a BCR, PSA kinetics as the PSADT are calculated based on the monthly PSA measurements during the first six months after the BCR. The values used to determine the BCR are included in the calculation of PSA kinetics as well. PSADT is calculated according to Pound et al. by the natural log of 2 (0.693) divided by the slope of the relationship between the log of PSA and time of PSA measurement (i.e. time from BCR) for each patient [33]. PSADT can also be assessed using the MSKCC PSADT calculator (https://www.mskcc.org/nomograms/prostate/psa_doubling_time) using the above definitions. | If BCR occurs up to 6 months later | 
| Incidence of Adverse Events [Safety and Tolerability] | Safety and tolerability assessed on the basis of adverse events, more precisely adverse events, serious adverse events, adverse reactions, and serious adverse reactions | From date the informed consent is signed until BCR occured and PSADT was calculated or when distant metastasis occurred (both with or without BCR) or date of death from any cause, whichever came first, assessed up to 7 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoplasm, prostate cancer, apalutamide, radical prostatectomy, randomized, high risk adenocarcinoma