Niraparib for Breast Cancer

(ZEST Trial)

Not currently recruiting at 260 trial locations

Overseen By EU GSK Clinical Trials Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: GlaxoSmithKline

Must be taking: Endocrine therapy

Must not be taking: PARP inhibitors, CDK4/6 inhibitors

Disqualifiers: Metastasis, Hypertension, Second malignancy, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 34 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness and safety of Niraparib for individuals with specific types of breast cancer. It targets those who have had their primary tumor removed and completed standard therapy. The trial focuses on HER2-negative breast cancer with either a BRCA gene mutation or triple-negative breast cancer with certain DNA markers. Participants will be randomly assigned to receive either Niraparib or a placebo, which contains no active drug. Ideal candidates have completed their main cancer treatment, have specific breast cancer types, and show no signs of cancer spread. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants with HR+ breast cancer stay on a stable regimen of certain endocrine therapies like anastrozole, letrozole, exemestane, and tamoxifen. If you are on other medications, the protocol does not specify, but you may need to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Niraparib is generally well-tolerated by patients. In past studies, most side effects were mild to moderate, such as fatigue, nausea, and low blood cell counts, and these issues were usually manageable with proper care.

Other trials have examined Niraparib in various cancer types, and the safety data supports its use. Niraparib is already approved for treating other cancers, like ovarian cancer, indicating a certain level of established safety.

Reports of more serious side effects, such as high blood pressure or anemia, are less common. Patients typically receive close monitoring during trials to manage any side effects.

Overall, evidence suggests that Niraparib is relatively safe, especially when healthcare professionals monitor patients during the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breast cancer?

Niraparib is unique because it targets cancer cells with specific DNA repair deficiencies, which sets it apart from traditional breast cancer treatments like chemotherapy or hormonal therapies. Most treatments for breast cancer focus on killing rapidly dividing cells or blocking hormones that fuel cancer growth. However, Niraparib is a PARP inhibitor that works by preventing cancer cells from repairing their DNA, which leads to their death. This targeted approach may offer a more effective option for patients with specific genetic mutations, like BRCA mutations, making researchers particularly excited about its potential in treating certain subtypes of breast cancer.

What evidence suggests that Niraparib might be an effective treatment for breast cancer?

Previous studies have shown promising results for Niraparib in treating certain types of breast cancer. One study found that patients with HER2-negative breast cancer experienced a significant reduction in tumor size, with 90.5% of patients seeing their tumors shrink by 30% or more after treatment with Niraparib. Another trial demonstrated Niraparib's activity against tumors, especially in patients with triple-negative breast cancer, a subtype that is difficult to treat. For patients with BRCA mutations, Niraparib had a response rate of 35%, confirming its effectiveness in this group. In this trial, participants will receive either Niraparib or a placebo, allowing researchers to further evaluate Niraparib's effectiveness for certain breast cancer patients, particularly those with specific genetic profiles. ^{1 2 6 7 8}

Who Is on the Research Team?

GSK Clinical Trials

Principal Investigator

GlaxoSmithKline

Are You a Good Fit for This Trial?

This trial is for individuals with HER2- breast cancer who have a BRCA gene mutation or triple-negative breast cancer (TNBC) and detectable circulating tumor DNA (ctDNA). They must have completed standard therapy, be in good physical condition (ECOG 0 or 1), and if HR+, on stable endocrine therapy. Exclusions include prior PARP inhibitor treatment, signs of metastasis, certain health conditions like uncontrolled hypertension, recent live vaccines, some other cancers, and pregnancy.

Inclusion Criteria

My breast cancer is stage I to III and has been surgically removed. It is either triple-negative or hormone receptor-positive/HER2-negative with a harmful BRCA mutation.

I have a tissue sample from my original tumor for DNA testing.

I am on a consistent hormone therapy for my HR+ breast cancer.

Exclusion Criteria

My high blood pressure is not well-controlled.

My cancer has spread or returned after a full check-up.

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)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Niraparib or Placebo

Up to approximately 34 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 8 years

What Are the Treatments Tested in This Trial?

Interventions

• Niraparib
• Placebo

Trial Overview The study tests the effectiveness and safety of Niraparib versus a placebo in patients with specific types of breast cancer after surgery or adjuvant therapy. It focuses on those with genetic mutations in BRCA or TNBC who show molecular disease through ctDNA presence.

How Is the Trial Designed?

Group I: Cohort1:Participants with tBRCAmut HER2-breast cancer(Independent of HR status,including HR+andTNBC) Experimental Treatment 2 Interventions

Eligible participants will receive either Niraparib or Placebo.

Group II: Cohort 2: Participants with tBRCAwt TNBC Experimental Treatment 2 Interventions

Eligible participants will receive either Niraparib or Placebo.

Niraparib is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Zejula for:

• Maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy
• Maintenance treatment of adults with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy

Approved in United States as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy
• Treatment of adults with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status

Approved in Canada as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

Who Is Running the Clinical Trial?

GlaxoSmithKline

Lead Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

In a phase III trial involving patients with advanced breast cancer and germline BRCA1/2 mutations, niraparib showed a median progression-free survival (PFS) of 4.1 months compared to 3.1 months for physician's choice chemotherapy, although the difference was not statistically significant (P = 0.86).

Despite the trial being halted due to issues with data assessment, niraparib demonstrated a 35% objective response rate, indicating its potential effectiveness in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study. Turner, NC., Balmaña, J., Poncet, C., et al.[2023]

In a phase 3 trial involving 553 patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly improved progression-free survival compared to placebo, with median durations of 21.0 months versus 5.5 months for patients with gBRCA mutations, and 12.9 months versus 3.8 months for those with homologous recombination deficiency.

While niraparib was effective, it was associated with moderate bone marrow toxicity, with common grade 3 or 4 adverse events including thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%), which were managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. Mirza, MR., Monk, BJ., Herrstedt, J., et al.[2022]

Niraparib, a PARP inhibitor for recurrent ovarian cancer, showed no significant changes in its pharmacokinetics when taken with a high-fat meal compared to fasting, indicating it can be safely taken with or without food.

The study demonstrated that niraparib was well-tolerated and had similar adverse events regardless of the meal condition, confirming its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. Moore, K., Zhang, ZY., Agarwal, S., et al.[2019]

In a pilot study of 21 patients with localized HER2-negative, BRCA-mutated breast cancer, neoadjuvant treatment with niraparib showed a high tumor response rate of 90.5% after 2 cycles, indicating strong antitumor activity.

Among those who continued treatment for 2-6 cycles, 40% achieved a pathological complete response, and no new safety concerns were reported, suggesting that niraparib is both effective and safe for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer. Spring, LM., Han, H., Liu, MC., et al.[2022]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib, administered at doses of 200 mg and 300 mg daily, was found to be tolerable in Japanese patients with advanced solid tumors, with only one case of dose-limiting toxicity observed.

The study demonstrated a favorable pharmacokinetic profile for niraparib, with dose-proportional increases in drug levels and some patients showing a partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study. Yonemori, K., Shimizu, T., Kondo, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9402431/

Neoadjuvant study of niraparib in patients with HER2- ... After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6 of 15) of patients who received only niraparib (2–6 cycles) had ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04915755

Study Details | NCT04915755 | Efficacy and Safety ... This study will assess the efficacy and safety of Niraparib in participants with either tumor mutation in the BRCA gene (tBRCAmut) HER2- breast cancer ...

3. aacr.org aacr.org/about-the-aacr/newsroom/news-releases/zest-trial-offers-insights-for-using-ctdna-to-predict-breast-cancer-recurrence/

ZEST Trial Offers Insights for Using ctDNA to Predict Breast ... The ZEST clinical trial, designed to evaluate niraparib (Zejula) for the prevention of breast cancer recurrence in patients with circulating tumor DNA (ctDNA),

4. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2735888

Open-label Clinical Trial of Niraparib Combined With ... Combination niraparib plus pembrolizumab offers promising antitumor activity in patients with advanced or metastatic triple-negative breast cancer.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8530899/

Niraparib for Advanced Breast Cancer with Germline BRCA1 ... The BRAVO trial confirms the activity of niraparib in patients with advanced breast cancer and germline BRCA1 and BRCA2 mutations, with a response rate of 35%, ...

6. aacrjournals.org aacrjournals.org/cancerres/article/82/4_Supplement/OT2-24-02/680327/Abstract-OT2-24-02-ZEST-Randomized-phase-III-study

Abstract OT2-24-02: ZEST: Randomized phase III study ... Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35788722/

Neoadjuvant study of niraparib in patients with HER2 ... After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6 of 15) of patients who received only niraparib (2-6 ...

8. stanfordhealthcare.org stanfordhealthcare.org/trials/e/NCT04915755.html

Efficacy and Safety Comparison of Niraparib to Placebo in ... This study will assess the efficacy and safety of Niraparib in participants with either tumor mutation in the BRCA gene (tBRCAmut) HER2- breast cancer ( ...