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

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)

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04915755

Acronym

ZEST

Enrollment

Registered

2021-06-07

Start date

2021-06-28

Completion date

2025-12-31

Last updated

2025-07-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms, Breast

Keywords

Niraparib, Breast cancer susceptibility gene, Human epidermal growth factor-2 negative (HER2), Breast cancer, Triple negative breast cancer (TNBC), Circulating tumor Deoxyribonucleic acid (ctDNA)

Brief summary

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.

Interventions

DRUGNiraparib

Niraparib will be administered.

DRUGPlacebo

Matching placebo will be administered

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

This is a double-blind study

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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).

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment Emergent Adverse Event (TEAEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)	Up to approximately 125 weeks	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose resulted in death, is life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, is a congenital anomaly/birth defect, other situations and is associated with liver injury or impaired liver function. SAEs are subsets of AEs. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state. AESI is any AE (serious or nonserious) that is of scientific and medical concern specific to niraparib for which ongoing monitoring and rapid communication by the Investigator to the Sponsor is warranted. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.
Number of Participants With TEAEs Leading to Death	Up to approximately 125 weeks	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state.Number of participants with TEAEs leading to death were reported.
Number of Participants With TEAEs Leading to Dose Modifications and Discontinuation of Study Treatment	Up to approximately 125 weeks	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAE is an event that emerged during treatment having been absent pretreatment or worsened relative to the pretreatment state. Number of participants with TEAEs leading to dose modifications (reduction and interruption/delay) and permanent discontinuation of study treatment were reported.
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status	Up to approximately 125 weeks	Number of participants with ECOG Performance Status was reported and was measured on 6-point grade scale 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of light or sedentary nature; Grade 2 - Ambulatory & capable of all self-care but unable to carry out any work activities. Up and about more than (\>) 50% of waking hours; Grade 3 -Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; Grade 4 -Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; Grade 5 -Dead. Data is presented as baseline grade, best case on-therapy, and worst-case on-therapy for the available participants.
Number of Participants With Worst-Case Post-Baseline (WCPB) Hematology Results Relative to Baseline	Up to approximately 125 weeks	Blood samples were collected for the analysis of hematology parameters. The summaries of worst-case change from baseline with respect to normal range was analyzed for only those laboratory tests that were not gradable by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5. The number of participants with decreases to low from baseline, changes to normal or no changes from baseline, and increases to high values have been presented. Baseline is defined as the latest non-missing pre-dose value, including those from unscheduled visits.
Number of Participants With Worst-Case Post-Baseline (WCPB) Clinical Chemistry Results Relative to Baseline	Up to approximately 125 weeks	Blood samples were collected for evaluation of clinical chemistry parameters. The summaries of worst case change from Baseline with respect to normal range have been presented for only those laboratory tests that are gradable by CTCAE v5.0. The number of participants with decreases to low, changes to normal or no changes from Baseline, and increases to high values have been presented. Baseline is defined as the latest non-missing pre-dose value, including those from unscheduled visits.
Number of Participants With Worst-Case Post-Baseline (WCPB) Vital Signs Results Relative to Baseline	Up to approximately 125 weeks	The abnormal vital sign ranges are: Pulse Rate (PR): Low \[\<60 beats per minute (bpm)\], Normal (60 bpm to 100 bpm), High (\>100 bpm); Temperature: Low (\<35 degree Celsius (°C)), Normal (35 C and 38 C), High (\>38 C); Systolic Blood Pressure (SBP): Low (\<90 millimeter of mercury (mmHg)), Normal (\>90 mmHg to \<120 mmHg), High (\>120 mmHg); Diastolic Blood Pressure (DBP): Low (\<60 mmHg), Normal (60 mmHg to 79 mmHg), High (\>80 mmHg). Participants were counted in the maximum worst case increase category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the To Normal or No Change category.
Number of Participants With Use of Concomitant Medications	Up to approximately 125 weeks	Number of participants who used concomitant medications is presented.

Countries

Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russia, South Africa, Spain, Switzerland, United Kingdom, United States

Participant flow

Pre-assignment details

The results presented are based on the data cut-off date of 28 June 2024. Those participants still benefiting from study drug in the opinion of their treating physician continue to receive study drug in Post Analysis Continued Treatment (PACT) phase and their data will be reported after they stop receiving treatment as per protocol.

Participants by arm

Arm	Count
Niraparib Participants with Either HER2-Negative BRCA-Mutated or Triple-Negative Breast Cancer received 200mg (two 100mg tablets) or 300 mg (three 100mg tablets) Niraparib tablet orally once daily depending on their body weight and platelet count, throughout each 28-day cycle starting on Cycle 1/Day 1 up to approximately 125 weeks.	18
Placebo Participants with Either HER2-Negative BRCA-Mutated or Triple-Negative Breast Cancer received Placebo tablet (two or three tablets) orally once a day depending on their body weight and platelet count, throughout each 28-day cycle starting on Cycle 1/Day 1 up to 64.7 weeks.	22
Total	40

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Ongoing for PACT	3	2
Overall Study	Other	7	11
Overall Study	Physician Decision	3	2
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Niraparib	Placebo	Total
Age, Continuous	58.1 YEARS STANDARD_DEVIATION 10.03	54.3 YEARS STANDARD_DEVIATION 14.22	56.0 YEARS STANDARD_DEVIATION 12.51
Race/Ethnicity, Customized All other races	6 Participants	3 Participants	9 Participants
Race/Ethnicity, Customized Unknown	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White	12 Participants	18 Participants	30 Participants
Sex: Female, Male Female	18 Participants	22 Participants	40 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 18	3 / 22
other Total, other adverse events	18 / 18	17 / 22
serious Total, serious adverse events	5 / 18	1 / 22

Outcome results

Primary

Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status

Number of participants with ECOG Performance Status was reported and was measured on 6-point grade scale 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of light or sedentary nature; Grade 2 - Ambulatory & capable of all self-care but unable to carry out any work activities. Up and about more than (\>) 50% of waking hours; Grade 3 -Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; Grade 4 -Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; Grade 5 -Dead. Data is presented as baseline grade, best case on-therapy, and worst-case on-therapy for the available participants.