Abstract OT2-24-02: ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy

Abstract Background: Following definitive treatment, there is no standard-of-care for patients (pts) with HR+HER2− breast cancer (BC) or TNBC beyond clinical monitoring for metastasis. Recurrence rates remain high for pts with a greater burden of residual disease after neoadjuvant chemotherapy. Detectable circulating tumor DNA (ctDNA) is also associated with a high risk of clinical relapse. However, there is no standard therapy for pts with detectable ctDNA who have not yet developed clinical metastasis. Niraparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), inhibits repair of DNA damage and stalled replication forks. PARPi showed clinical activity in pts with TNBC, with increased responses in homologous recombination deficient (HRd) tumors. HRd is common in TNBC, including in pts with wild-type or mutated tumor BRCA (tBRCAwt and tBRCAm). Neoadjuvant niraparib showed clinical activity in tBRCAm HER2− BC. This study will assess niraparib in pts with tBRCAm HER2− BC or tBRCAwt TNBC who have detectable ctDNA after completion of definitive therapy. Trial Design: ZEST (NCT04915755) is a multicenter, multicohort, Phase 3, double-blind, placebo-controlled study in pts with tBRCAm HER2− BC (HR+ with concomitant endocrine therapy and TNBC; Cohort 1) or tBRCAwt TNBC (Cohort 2) with detectable ctDNA following surgery or completion of adjuvant chemotherapy and radiotherapy. Pts who previously completed definitive therapy at any time are eligible for ctDNA monitoring and potential enrollment in the trial following detection of ctDNA. HR+/HER2− pts must have known tBRCAm to qualify for ctDNA screening. For all other pts, tBRCA status will be confirmed in those with detectable ctDNA. HRd status will be assessed at prescreening; pts with tBRCAwt TNBC and HRd will be allocated to Cohort 2. Pts with detectable ctDNA and no recurrence on staging scans will be randomized 1:1 to receive niraparib or placebo. Niraparib will be given orally once daily at a dose of 300 mg; pts with body weight <77 kg, platelet count <150,000/µL, or with moderate hepatic impairment will receive 200 mg. Pts will be monitored with CT imaging every 12 weeks for the first 2 years, then every 6 months. Treatment will continue until disease recurrence, death, or unacceptable toxicity. All pts will be stratified by time from last intervention to randomization (<6 vs ≥6 months) and stage of BC (stage I/II vs III). Pts in Cohort 1 will also be stratified by HR status and pts in Cohort 2 by prior use of adjuvant capecitabine. Table 1 shows key eligibility criteria. The primary endpoint is disease-free survival for niraparib versus placebo; secondary objectives include overall survival, time to progression on next anticancer therapy, distant recurrence-free survival, safety, tolerability, and health-related quality of life. The primary efficacy analyses will be based on all randomized pts. Safety will be analyzed in all randomized pts who receive ≥1 dose of niraparib. Target accruals are 200 and 600 pts in Cohorts 1 and 2, respectively. The trial has begun enrolling. Funding: GlaxoSmithKline (GSK) study 213831; NCT04915755. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Key eligibility criteriaInclusion criteriaExclusion criteria• Age ≥18 years• Prior treatment with a poly(ADP-ribose) polymerase inhibitor. • Current treatment with a cyclin-dependent kinase 4 and 6 inhibitor or endocrine therapy other than anastrozole, letrozole, exemestane, and tamoxifen. • Any sign of local recurrence or metastasis. • Lack of definitive response to preoperative chemotherapy by pathologic or radiographic evaluation, in cases where preoperative chemotherapy was administered. • Live vaccine therapy within 30 days of planned start of study randomization. • A second primary malignancy, except (a) adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ 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. • Pregnancy, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment • History of human immunodeficiency virus • Known history of myelodysplastic syndrome or acute myeloid leukemia• Stage I-III breast cancer, with surgical resection of the primary tumor, that is confirmed as either: o triple-negative breast cancer, irrespective of tumor breast cancer gene (tBRCA) status, or o Hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- with a documented tBRCA mutation. • Completed prior standard therapy for curative intent including all of the following, if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy. • Stable regimen of endocrine therapy, if indicated, for ≥3 months prior to enrollment (HR+ only) • Detectable circulating tumor DNA by central Signatera 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 Citation Format: Nicholas C Turner, David W Cescon, Sibylle Loibl, Wolfgang Janni, Hope Rugo, Judith Balmaña, Cheynna Crowley, Jon Chung, Giulia Fucli, Erin Hofstatter, Tara Frenkl, Melinda L Telli. ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-02.

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