A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer (MAGNITUDE)

• ClinicalTrials.gov Identifier: NCT03748641
• Recruitment Status: Active, not recruiting
• First Posted: November 21, 2018
• Results First Posted: October 4, 2023
• Last Update Posted: April 25, 2024
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: November 19, 2018
• First Posted Date: November 21, 2018
• Results First Submitted Date: September 8, 2023
• Results First Posted Date: October 4, 2023
• Last Update Posted Date: April 25, 2024
• Actual Study Start Date: January 25, 2019
• Actual Primary Completion Date: October 8, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2023)

Cohort 1: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to 32 months ]

As per BICR, rPFS is time interval from the date of randomization to radiographic progression or death, whichever occurs first. Radiographic progression was determined by: 1) progression of soft tissue lesions measured by computerized tomography (CT) or magnetic resonance imaging (MRI) as per response evaluation criteria in solid tumors (RECIST) 1.1; 2) Progression of bone lesions observed by bone scan based on prostate cancer working group 3 (PCWG3) criteria. PCWG3 criteria: bone progression was confirmed by subsequent scan greater than or equal to (>=) 6 weeks later. Week 8 scan was baseline to which all subsequent scans were compared to determine progression. Confirmatory scan >=2 new lesions indicate progression; scan does not show >= 2 new lesions means no progression. If Week 8 scan less than (<) 2 new bone lesions compared to baseline, the initial scan >=2 new lesions compared to Week 8 scan indicates progression if confirmed by subsequent scan >=6 weeks later.

Original Primary Outcome Measures (submitted: November 19, 2018)

Radiographic Progression Free Survival (rPFS) [ Time Frame: Approximately 40 months ]

rPFS is defined as time from date of randomization to date of radiographic progression or death, whichever occurs first. Radiographic progression will be evaluated by Prostate Cancer Working Group 3 (PCWG3) as follows: progression of soft tissue lesions measured by computed tomography/magnetic resonance imaging as per response evaluation criteria in solid tumors (RECIST) 1.1; progression by bone lesions observed by bone scan and based on PCWG3. As per criteria, any bone progression must be confirmed by a subsequent scan greater than or equal to (>=) 6 weeks later. Week 8 scan will be baseline to which all subsequent scans will be compared to determine progression. Bone progression is defined as one of the following: participants whose confirmatory scan shows >=2 new lesions will be considered to have bone scan progression and who did not show >= 2 new lesions will not be considered to have bone scan progression when compared to Week 8 scan.

Current Secondary Outcome Measures (submitted: September 8, 2023)

• Cohort 1: Overall Survival (OS) [ Time Frame: Up to 97 months ]
• Cohort 1: Time to Symptomatic Progression [ Time Frame: Up to 97 months ]
• Cohort 1: Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Up to 97 months ]
• Observed Plasma Concentrations of Niraparib [ Time Frame: Up to 97 months ]
• Observed Plasma Concentrations of Abiraterone [ Time Frame: Up to 97 months ]
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to 96 months ]
• Number of Participants With Treatment-Emergent Adverse Events by Severity [ Time Frame: Up to 96 months ]
• Number of Participants With Abnormalities in Laboratory Values [ Time Frame: Up to 96 months ]

Original Secondary Outcome Measures (submitted: November 19, 2018)

• Overall survival (OS) [ Time Frame: Approximately up to 73 months ]
  OS is defined as the time from date of randomization to date of death from any cause.
• Time to Chronic Opioid Use [ Time Frame: Approximately up to 73 months ]
  Time to chronic opioid use (oral opioid use for >=3 weeks; parenteral opioid use for >=7 days) is defined as the time from date of randomization to the first date of chronic opioid use.
• Time to Pain Progression [ Time Frame: Approximately up to 73 months ]
  Time to pain progression is defined as the time from date of randomization to the date of the first observation of pain progression. Pain progression is defined as an increase by at least 2 points from baseline in the brief pain inventory-short form (BPI-SF) worst pain intensity (item 3) observed at 2 consecutive evaluations >= 3 weeks apart, or Initiation of short or long-acting opioids for pain.
• Time to Initiation of Cytotoxic Chemotherapy [ Time Frame: Approximately up to 73 months ]
  Time to initiation of cytotoxic chemotherapy is defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.
• Observed Plasma Concentrations of Niraparib [ Time Frame: Cycle 2: Day 1 (Predose, between 1 to 3 and 3 to 6 hours postdose); Cycle 3: Day 1 (Predose); Cycles 4 to 7: Day 1 (Predose or at least 3 hours postdose); each Cycle of 28 days ]
  Observed plasma concentrations of niraparib with descriptive statistics will be reported.
• Observed Trough Plasma Concentrations of Abiraterone [ Time Frame: Cycles 2 and 3 (Each Cycle of 28 days): Day 1 (Predose) ]
  Observed trough plasma concentrations of abiraterone with descriptive statistics will be reported.
• Number of Participants with Treatment-Emergent Adverse events (TEAEs) [ Time Frame: Approximately up to 73 months ]
  An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. AE does not necessarily have a causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug.
• Number of Participants with Treatment-Emergent Adverse events by Severity [ Time Frame: Approximately up to 73 months ]
  An adverse event is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. AE does not necessarily have a causal relationship with intervention. AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal product. TEAEs are those events that occur or worsen on or after first dose of study drug through 30 days after last dose of study drug. Severity criteria includes grades:1) Mild: easily tolerated, causing minimal discomfort and no interference with everyday activities 2) Moderate: sufficient discomfort to cause interference with normal activity 3) Severe: extreme distress, significant impairment of functioning/incapacitation. Prevents everyday activities 4) Life-threatening: urgent intervention indicated 5) Death
• Number of Participants with Laboratory Abnormalities as Measure of Safety [ Time Frame: Approximately up to 73 months ]
  Number of participants with laboratory abnormalities (hematology, serum chemistry and liver function test) will be determined.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer
• Official Title: A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Metastatic Prostate Cancer
• Brief Summary: The purpose of this study is to evaluate the effectiveness of niraparib in combination with abiraterone acetate plus prednisone (AAP) compared to AAP and placebo.
• Detailed Description: This study will assess efficacy and safety of niraparib in combination with AAP for the treatment of participants with metastatic castration resistant prostate cancer. Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. AA is a pro-drug of abiraterone and selectively inhibits the enzyme 17 alpha-hydroxylase/C17,20-lyase (CYP17), which is found in the testes and adrenals, as well as in prostate tissues and tumors. In participants with metastatic prostate cancer, DNA-repair anomalies are identified in approximately 15 percent (%) to 20% of tumors. The study will consist of 5 phases: a prescreening phase for biomarker evaluation only, a screening phase, a treatment phase, a follow up phase, and an extension phase (either open-label extension [OLE] or long-term extension [LTE]). During the prescreening phase participants will be evaluated for homologous recombination repair (HRR) gene alteration status and then will be assigned to one of the 2 cohorts based on their biomarker status. Treatment will be administered daily and is planned to be continuous until disease progression, unacceptable toxicity, death, or the sponsor terminates the study. Efficacy, pharmacokinetics, biomarkers, participants reported outcomes and safety will be assessed. The total duration of study will be approximately 66 months.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Castration-Resistant Prostatic Cancer

Intervention

• Drug: Niraparib
  Participants will receive niraparib 200 mg capsules once daily.
  Other Name: JNJ-64091742
• Drug: Abiraterone Acetate
  Participants will receive AA 1000 mg tablets once daily.
• Drug: Prednisone
  Participants will receive prednisone 10 mg tablets daily.
• Drug: Placebo
  Participants will receive matching placebo once daily.
• Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)
  Participants will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets once daily.

Study Arms

• Experimental: Cohort 1: Participants with mCRPC and HRR Gene Alteration
  Participants with L1 metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alteration will receive combination of niraparib 200 milligrams (mg) or matching placebo and abiraterone acetate (AA) 1000 mg plus prednisone 10 mg. In the open label extension (OLE) phase participants earlier receiving the combination of niraparib and AAP may continue to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg and those receiving placebo and AAP may cross over depending on the outcome of study to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg.
  Interventions:

  • Drug: Niraparib
  • Drug: Abiraterone Acetate
  • Drug: Prednisone
  • Drug: Placebo
• Experimental: Cohort 2: Participants with mCRPC and No HRR Gene Alteration
  Participants with L1 mCRPC and no HRR Gene alteration will receive combination of niraparib 200 mg or matching placebo and AA 1000 mg plus prednisone 10 mg. In the OLE phase participants earlier receiving the combination of niraparib and AAP may continue to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg and those receiving placebo and AAP may cross over depending on the outcome of study to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg.
  Interventions:

  • Drug: Niraparib
  • Drug: Abiraterone Acetate
  • Drug: Prednisone
  • Drug: Placebo
• Experimental: Cohort 3 (Open-label): Participants with mCRPC
  Participants with mCRPC will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets plus prednisone 10 mg.
  Interventions:

  • Drug: Prednisone
  • Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 4, 2021): 765
• Original Estimated Enrollment (submitted: November 19, 2018): 1000
• Estimated Study Completion Date: February 19, 2027
• Actual Primary Completion Date: October 8, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• HRR gene alteration (as identified by the sponsor's required assays) as follows:

  1. Cohort 1: positive for HRR gene alteration
  2. Cohort 2: not positive for DRD (that is, HRR gene alteration)
  3. Cohort 3: eligible by HRR status
• Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI)
• Metastatic prostate cancer in the setting of castrate levels of testosterone less than or equal to (<=) 50 nanogram per deciliter (ng/dL) on a gonadotropin releasing hormone analog (GnRHa) or bilateral orchiectomy
• Able to continue GnRHa during the study if not surgically castrate
• Score of <= 3 on the brief pain inventory-short form (BPI-SF) question number 3 (worst pain in last 24 hours)

Exclusion Criteria:

• Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor
• Systemic therapy (that is, novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of abiraterone acetate plus prednisone [AAP] prior to randomization) in the metastatic castration-resistant prostate cancer (mCRPC) setting; or AAP outside of the mCRPC setting
• Symptomatic brain metastases
• History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Other prior malignancy (exceptions: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) <= 2 years prior to randomization, or malignancy that currently requires active systemic therapy

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Russian Federation, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03748641
• Other Study ID Numbers: CR108534; 2017-003364-12 ( EudraCT Number ); 64091742PCR3001 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Janssen Research & Development, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Janssen Research & Development, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: April 2024