An Efficacy and Safety Study of Apalutamide (JNJ-56021927) in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Participants With Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC)

Study Overview
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Brief Summary
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The purpose of this study is to compare the radiographic progression-free survival (rPFS) of apalutamide in combination with abiraterone acetate (AA) plus prednisone or prednisolone (AAP) and AAP in participants with chemotherapy-naive (participants who did not receive any chemotherapy [treatment of cancer using drugs]) metastatic castration-resistant prostate cancer (mCRPC) (cancer of prostate gland [gland that makes fluid that aids movement of sperm]).

Detailed Description
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This is a randomized (study drug assigned by chance), double-blind (neither the Investigator nor the participant know the treatment) placebo-controlled and multicenter (when more than 1 hospital or medical school team work on a medical research study) study to determine if participants with chemotherapy-naive mCRPC will benefit from the addition of apalutamide to AAP compared with AAP alone. The study consists of 3 phases: Screening phase; Treatment phase, and Follow-up phase. At the final analysis, the study will be unblinded. After the Independent Data Monitoring Committee (IDMC) review and the sponsor's subsequent decision participants will be offered to receive treatment either in the Open-Label Extension Phase or the Long-Term Extension Phase of study. Participants' safety will be monitored throughout the study.

Official Title
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A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC)

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Apalutamide
* Drug: Abiraterone acetate
* Drug: Prednisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adenocarcinoma of the prostate Metastatic disease as documented by technetium-99m (99mTc) bone scan or metastatic lesions by computed tomography (CT) or magnetic resonance imaging (MRI) scans (visceral or lymph node disease). If lymph node metastasis is the only evidence of metastasis, it must be greater than or equal to (>=) 2 centimeter (cm) in the longest diameter Castration-resistant prostate cancer demonstrated during continuous androgen deprivation therapy (ADT), defined as 3 rises of PSA, at least 1 week apart with the last androgen deprivation therapy (PSA) >= 2 nanogram per milliliters (ng/mL) Participants who received a first generation anti-androgen (eg, bicalutamide, flutamide, nilutamide) must have at least a 6-week washout prior to randomization and must show continuing disease (PSA) progression (an increase in PSA) after the washout period Prostate cancer progression documented by prostate-specific antigen (PSA) according to the Prostate Cancer Clinical Trials Working Group (PCWG2) or radiographic progression of soft tissue according to modified Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) modified based on PCWG2, or radiographic progression of bone according to PCWG2 Participants who cross-over from Prednisone alone to open-label apalutamide plus AAP should still be in the double-blind phase of the study, should be receiving AAP alone and should have ECOG 0-1-2. Exclusion Criteria: Small cell or neuroendocrine carcinoma of the prostate Known brain metastases Prior chemotherapy for prostate cancer, except if administered in the adjuvant/neoadjuvant setting Previously treated with ketoconazole for prostate cancer for greater than 7 days Therapies that must be discontinued or substituted at least 4 weeks prior to randomization include the following: a) Medications known to lower the seizure threshold, b) Herbal and non-herbal products that may decrease PSA levels (example [eg], saw palmetto, pomegranate) or c) Any investigational agent At Screening need for parenteral or oral opioid analgesics (eg, codeine, dextropropoxyphene)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: AAP and apalutamide<br>Participants will receive apalutamide 240 milligram (mg) (4*60 mg tablets) and abiraterone acetate (AA) 1000 mg (4*250 mg tablets) once daily on an empty stomach and 5 mg prednisone (P), AAP, twice daily, until disease progression, unacceptable toxicity or end of treatment, whichever occurs first. After unblinding participants will be offered further treatment as defined in the Open-Label Extension (OLE) or Long-Term Extension (LTE) phase (AAP + open label apalutamide or AAP alone). | Drug: Apalutamide<br>* Participants will receive 240 mg (4*60 mg tablets) of apalutamide once daily orally.<br>Drug: Abiraterone acetate<br>* Participants will receive 1000 mg (4*250 mg tablets) of abiraterone acetate (AA) once daily orally.<br>* Other names: ZYTIGA;Drug: Prednisone<br>* Participants will receive 5 mg tablet of prednisone twice daily orally.<br>|
| Placebo Comparator: Group 2: AAP and Placebo<br>Participants will receive matching Placebo of apalutamide and abiraterone acetate (AA) 1000 mg (4*250 mg tablets) once daily on an empty stomach and 5 mg prednisone (P), AAP, twice daily until disease progression, unacceptable toxicity or end of treatment, whichever occurs first. After unblinding participants will be offered further treatment as defined in the OLE or LTE phase (AAP + open label apalutamide or AAP alone). | Drug: Abiraterone acetate<br>* Participants will receive 1000 mg (4*250 mg tablets) of abiraterone acetate (AA) once daily orally.<br>* Other names: ZYTIGA;Drug: Prednisone<br>* Participants will receive 5 mg tablet of prednisone twice daily orally.<br>Drug: Placebo<br>* Participants will receive matching placebo to apalutamide once daily orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-free Survival (rPFS) | The rPFS was defined as the time from randomization to the occurrence of one of the following: 1) a participant was considered to have progressed by bone scan if - a) the first bone scan with greater than or equal to (>=) 2 new lesions compared to baseline was observed in less than (<) 12 weeks from randomization and was confirmed by a second bone scan taken >=6 weeks later showing >=2 additional new lesions (a total of >=4 new lesions compared to baseline), b) the first bone scan with >=2 new lesions compared to baseline was observed in >=12 weeks from randomization and the new lesions were verified on the next bone scan >=6 weeks later (a total of >=2 new lesions compared to baseline); 2) progression of soft tissue lesions measured by computerized tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. | Up to 3 years and 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The OS was defined as the time from randomization to date of death from any cause. | Up to 5 years and 10 months | 
| Time to Chronic Opioid Use | Time to chronic opioid use was defined as the time from date of randomization to the first date of opioid use. | Up to 5 years and 10 months | 
| Time to Initiation of Cytotoxic Chemotherapy | Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy. | Up to 5 years and 10 months | 
| Time to Pain Progression | Time to pain progression: time from randomization to first date that participant either experienced an increase by 2 points from baseline in Brief Pain Inventory Short Form (BPI-SF) worst pain intensity item (item 3) or Case Report Form (CRF) pain, observed at 2 consecutive evaluations >=4 wks apart, or initiation of chronic opioids as defined in time to chronic opioid use, whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions. Item 3(worst pain intensity) asks participants to rate worst pain in prior 7-days on a 0-10 numeric rating scale, where 0 indicates No pain and 10 indicates Pain as bad as you can imagine. A lower score is better.CRF pain refers to participant's response to global pain assessment How would you rate your pain over the past 7 days?with a scale of 0(No pain) to 10(Pain as bad as you can imagine),that is systematically reported and recorded on the eCRF. | Up to 5 years and 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatic neoplasms, JN56021927, ZYTIGA, Prednisone, Abiraterone acetate, Apalutamide