Study of Abiraterone Acetate Plus ADT Versus APALUTAMIDE Versus Abiraterone and APALUTAMIDE in Patients With Advanced Prostate Cancer With Non-castrate Testosterone Levels

Study Overview
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Brief Summary
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Evaluation of the activity, safety and patients reported outcome of ADT plus abiraterone, abiraterone plus APALUTAMIDE (a second-generation antiandrogen) or APALUTAMIDE alone in hormone naïve locally advanced or metastatic prostate cancer which ADT was indicated.

Detailed Description
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Based on the current guidelines, ADT alone or combined with is antiandrogens are considered the appropriate active therapy for the patient population planned for this study. Recent data showed that chemotherapy also benefit patients in this setting. Even though, there is a clear unmet medical need for alternative treatment option in metastatic hormone sensitive prostate cancer (mHSPC). Treatments that can delay disease progression, and are associated with less comorbidities would be of significant clinical benefit in this patient population. The study is designed to assess the efficacy and safety of abiraterone plus APALUTAMIDE (a second-generation antiandrogen) or APALUTAMIDE alone without castration side effects and the other arm a combination of ADT and abiraterone; this last arm is to reflect an Abiraterone ongoing pivotal trial (LATITUDE), that assess the efficacy of adding abiraterone to castration in this setting of patients. Abiraterone had already showed clinical benefit in CRPC patients without prior chemotherapy.

Official Title
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Phase II Randomized Study of Abiraterone Acetate Plus ADT Versus APALUTAMIDE Versus Abiraterone and APALUTAMIDE in Patients With Advanced Prostate Cancer With Non-castrate Testosterone Levels

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Apalutamide
* Drug: Abiraterone
* Drug: ADT
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed prostate adenocarcinoma; Hormone naïve patients with indication to ADT in the following settings: Advanced loco-regional disease not amenable to curative local therapy (surgery or radiotherapy): T category T3/4 or node positive Biochemical relapse after primary treatment (surgery or radiotherapy): patients in whom primary therapy is not appropriate or feasible with Previously treated with radical surgery and/or radiotherapy, now relapsing with at least one of the criteria: PSA >= 4 ng/ml and rising with doubling time less than 10 months. or PSA >= 20 ng/ml or N+ or M+ Newly diagnosed metastatic disease: Tany Nany M+ Patient is asymptomatic or moderately symptomatic regarding bone symptoms, i.e., no need for palliative radiation or radionuclide therapy; Non-castration level of testosterone > 230ng/dL (> 8 nmol/L); Baseline level of prostatespecific antigen (PSA) > 2ng/dL; ECOG performance status of 0 to 2; Adequate hematologic, hepatic and renal function: hemoglobin > 10 g/dL, neutrophils > 1.5×109 / L, platelets> 100×109 / L; total bilirubin < 1.5x upper limit of normal (ULN); alanine (ALT) and aspartate (AST) aminotransferase < 2.5 x ULN; serum creatinine < 1.5x ULN; potassium > 3.5 mM; No previous cancer (except treated basal-cell skin cancer); Written informed consent obtained prior to any study procedure; Men age 18 years and older; Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant. Exclusion Criteria: Prostate adenocarcinoma with neuroendocrine differentiation or small cell histology; Biochemical recurrence without evidence of clinical or radiological disease; Use of hormonal therapy or chemotherapy prior to randomization. Exception is courses of hormone therapy for localised disease must have been completed at least 12 months previously. It can have been given as adjuvant or neoadjuvant therapy. Prior radiation therapy for a primary tumour within the 3 months before enrollment or for the treatment of metastases; Known or suspected brain or skull metastases or leptomeningeal metastatic disease; Any concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study; Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 28 days of Cycle 1 Day 1 or currently enrolled in an investigational study; Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction; Current or prior treatment with anti-epileptic medications for the treatment of seizures; Impaired cardiac function, including any of the following: Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP ≥95 mmHg); Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events or history of cardiac failure in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease; Existing atrial fibrillation with or without pharmacotherapy. Other cardiac arrhythmia requiring pharmacotherapy; 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); Specific underlying conditions for oral agents. For example: impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of abiraterone or APALUTAMIDE (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) General excluded medications (e.g., relevant to cytochrome P450 interactions) Use of prescription drugs within 14 days prior to dosing or over-the-counter (OTC) medication within 7 days prior to dosing; Consumption of grapefruit product or St John's wort within 7 days prior to dosing; G-CSF, GM-CSF, erythropoietin, etc; Coumadin; Drugs which may cause QT prolongation; Known sensitivity to drugs or metabolites from similar classes; Known or suspected contraindications or hypersensitivity to APALUTAMIDE, bicalutamide or GnRH agonists or any of the components of the formulations; Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject's participation in this study.

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 |
| --- | --- |
| Active Comparator: Abiraterone acetate + Prednisone + ADT (Goserelin)<br>Abiraterone administered at a single 1000 mg daily oral dose (4 x 250-mg tablets) Prednisone administered at a 5 mg twice daily oral dose Goserelin administered as subcutaneous injections of 10.8mg every 3 months | Drug: Apalutamide<br>* APALUTAMIDE 240-mg orally once daily (4 x 60-mg tablets) will be administered on a continual basis. For the purpose of scheduling the study assessments and treatment compliance a treatment cycle is defined as 28 days.<br>Drug: Abiraterone<br>* Abiraterone acetate 1,000 mg (four 250 mg tablets) should be taken orally once daily, in combination with oral dose prednisone 5mg twice daily continuously. For the purpose of scheduling the study assessments and treatment compliance a treatment cycle is defined as 28 days<br>Drug: ADT<br>* Dosing of goserelin (dose and frequency of administration) will be consistent with the prescribing information and should only be adjusted if clinically indicated to achieve and maintain subcastrate concentrations of testosterone (50 ng/dL or 1.7 nM).<br>* Other names: Goserelin;|
| Experimental: APALUTAMIDE monotherapy<br>o APALUTAMIDE administered at a single 240 mg daily oral dose (4 x 60 mg tablets) | Drug: Apalutamide<br>* APALUTAMIDE 240-mg orally once daily (4 x 60-mg tablets) will be administered on a continual basis. For the purpose of scheduling the study assessments and treatment compliance a treatment cycle is defined as 28 days.<br>|
| Experimental: Abiraterone acetate + Prednisone + APALUTAMIDE<br>Abiraterone administered at a single 1000 mg daily oral dose (4 x 250 mg tablets) Prednisone administered at a 5 mg twice daily oral dose APALUTAMIDE administered at a single 240 mg daily oral dose (4 x 60 mg tablets) | Drug: Apalutamide<br>* APALUTAMIDE 240-mg orally once daily (4 x 60-mg tablets) will be administered on a continual basis. For the purpose of scheduling the study assessments and treatment compliance a treatment cycle is defined as 28 days.<br>Drug: Abiraterone<br>* Abiraterone acetate 1,000 mg (four 250 mg tablets) should be taken orally once daily, in combination with oral dose prednisone 5mg twice daily continuously. For the purpose of scheduling the study assessments and treatment compliance a treatment cycle is defined as 28 days<br>Drug: Prednisone<br>* Subjects will receive prednisone 10mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients that achieves an undetectable PSA level, defined as ≤ 0.2 ng/mL |  | Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA progression rate | Determination of PSA progression rate among the three experimental arms | Week 25 | 
| Comparison of PSA progression rate | Comparison of PSA progression rate among the three experimental arms | Week 25 | 
| PSA response of 50 and 80% | Determination of PSA response of 50 and 80% among the three experimental arms | Week 25 | 
| Comparison of PSA response of 50 and 80% | Comparison of PSA response of 50 and 80% among the three experimental arms | Week 25 | 
| Maximum PSA declines | Determination of maximum PSA declines among the three experimental arms | Baseline up to week 25 to 52 | 
| Overall PSA change | Determination of overall PSA change among the three experimental arms | Baseline up to week 25 to 52 | 
| Hormonal levels during treatment |  | Baseline up to week 25 | 
| Comparison of hormonal levels during treatment | Comparison of hormonal levels during treatment among the three experimental arms | Baseline up to week 25 | 
| Evaluation of bone mineral density according to RECIST 1.1 |  | Week 25 | 
| Comparison of bone mineral density according to RECIST 1.1 between three experimental groups |  | Week 25 | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | Baseline to 2 years of follow-up | 
| Number of participants with pain progression assessed by BPI-SF of three experimental arms |  | Baseline up to week 25 | 
| Number of participants in opioid use during treatment among three experimental arms |  | Baseline up to week 25 | 
| Comparison of pain progression assessed by opioid use | Comparison of pain progression assessed by opioid use between the experimental arms | Baseline up to week 25 | 
| Comparison of pain progression assessed by BPI-SF questionnaire | Comparison of pain progression assessed by BPI-SF between the experimental arms | Baseline up to week 25 | 
| Quality of life assessed by FACT-P questionnaire | Quality of life assessed by FACT-P questionnaire of the experimental arms | Baseline up to week 25 | 
| Comparison of quality of life assessed by FACT-P questionnaire | Comparison of quality of life assessed by FACT-P questionnaire between the experimental arms | Baseline up to week 25 | 
| Radiographic progression-free survival (rPFS) | Radiographic progression-free survival (rPFS) among the experimental arms | Week 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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apalutamide, abiraterone, prostate cancer