Efficacy and Safety Comparison of Niraparib to Placebo in Participants With Human Epidermal Growth Factor 2 Negative (HER2-) Breast Cancer Susceptibility Gene Mutation (BRCAmut) or Triple-Negative Breast Cancer (TNBC) With Molecular Disease

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of Niraparib in participants with either tumor mutation in the BRCA gene (tBRCAmut) HER2- breast cancer (Independent of hormone receptor [HR] status, including HR positive [+] and TNBC) or tumor BRCA wild type (tBRCAwt) TNBC with molecular disease based on the presence of circulating tumor Deoxyribonucleic acid (ctDNA) following surgery or completion of adjuvant therapy.

Official Title
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A Randomized Phase 3 Double-Blinded Study Comparing the Efficacy and Safety of Niraparib to Placebo in Participants With Either HER2-Negative BRCA-Mutated or Triple-Negative Breast Cancer With Molecular Disease Based on Presence of Circulating Tumor DNA After Definitive Therapy (ZEST)

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: Niraparib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage I to III breast cancer with surgical resection of the primary tumor that is confirmed to be either: TNBC, irrespective of BRCA status or HR+/HER2- breast cancer with a known and documented deleterious or suspected deleterious tBRCA mutation. Estrogen receptor (ER) and/or progesterone receptor (PgR) negativity is defined as immunohistochemistry (IHC) nuclear staining less than (<) 1 percentage (%), or by Allred scoring system where TNBC is defined to be 0 out of 8 or 2 out of 8, or staining in <1 % of cancer cells. Completed prior standard therapy for curative intent. Participants with HR+ breast cancer must be on a stable regimen of endocrine therapy. Detectable ctDNA as measured by central testing. An archival tumor tissue specimen of the primary tumor sufficient in quality and quantity for ctDNA assay design and tBRCA and Homologous recombination deficiency (HRD) testing is required. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: Prior treatment with a Poly Adenosine-diphosphate Ribose Polymerase (PARP) inhibitor. Current treatment with a Cyclin-dependent kinase (CDK)4/6 inhibitor or endocrine therapy other than anastrozole, letrozole, exemestane, and tamoxifen with or without ovarian suppression. Participants have any sign of metastasis or local recurrence after comprehensive assessment conducted per protocol. Participants have shown no definitive response to preoperative chemotherapy by pathologic, radiographic or clinical evaluation, in cases where preoperative chemotherapy was administered. Participants have inadequately treated or controlled hypertension. Participants have received live vaccine within 30 days of planned start of study randomization. Participants have a second primary malignancy. Exceptions are the following: (a) Adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal carcinoma in situ (DCIS) of the breast, Stage I Grade 1 endometrial carcinoma. (b) Other solid tumors and lymphomas (without bone marrow involvement) diagnosed >=5 years prior to randomization and treated with no evidence of disease recurrence and for whom no more than 1 line of chemotherapy was applied. Participant is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment (except France). Participant is immunocompromised. Participants with splenectomy are allowed. Participants with known human immunodeficiency virus (HIV) are allowed if they meet protocol-defined criteria. Participants have a known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Cohort1:Participants with tBRCAmut HER2-breast cancer(Independent of HR status,including HR+andTNBC)<br>Eligible participants will receive either Niraparib or Placebo. | Drug: Niraparib<br>* Niraparib will be administered.<br>Drug: Placebo<br>* Matching placebo will be administered<br>|
| Experimental: Cohort 2: Participants with tBRCAwt TNBC<br>Eligible participants will receive either Niraparib or Placebo. | Drug: Niraparib<br>* Niraparib will be administered.<br>Drug: Placebo<br>* Matching placebo will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment emergent adverse event (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) | Number of participants with TEAEs, SAEs, and AESIs will be assessed. | Up to approximately 34 months | 
| Number of participants with clinically significant changes in Eastern Co-operative Oncology Group (ECOG) performance status | The performance status will be assessed using ECOG scale, where Grade 0 (fully active), Grade 1 (restricted in physically strenuous activity), Grade 2 (ambulatory and capable of all self-care), Grade 3 (capable of only limited self-care) and Grade 4 (completely disabled). Change in ECOG performance from baseline will be assessed. | Up to approximately 34 months | 
| Number of participants with clinically significant changes in relevant laboratory parameters | Number of participants with clinically significant changes in hematology and clinical chemistry parameters will be assessed. | Up to approximately 34 months | 
| Number of participants with clinically significant changes in vital signs | Number of participants with clinically significant changes in vital signs will be assessed. | Up to approximately 34 months | 
| Number of participants with use of concomitant medications | Number of participants using concomitant medications will be assessed. | Up to approximately 34 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Niraparib, Breast cancer susceptibility gene, Human epidermal growth factor-2 negative (HER2), Breast cancer, Triple negative breast cancer (TNBC), Circulating tumor Deoxyribonucleic acid (ctDNA)