Effectiveness of niraparib plus aromatase inhibitors (AI) for germinal BRCA1/2-mutated (gBRCAm) or homologous recombination deficient (HRD), hormone receptor (HR) plus /human epidermal growth factor receptor 2 (HER2)-advanced breast cancer (ABC). The LUZERN Strategy

Niraparib is a potent and orally active poly(ADP-ribose)polymerase (PARP)1/2 inhibitor that has demonstrated clinical activity in patients (pts) with advanced gBRCAm ovarian and breast cancers. About 5% of HR+/HER2- breast cancer pts result gBRCAm and 10-20% are HRD. This study will evaluate the efficacy and safety of niraparib plus AI in gBRCAm or HRD, HR+/HER2- pretreated ABC pts. This is a multicenter, open-label, single-arm, two-cohort, phase II trial. The cohort A and the exploratory cohort B will include gBRCAm and HRD, HR+/HER2- ABC pts, respectively. Pts will receive niraparib (200 or 300 mg depending on baseline body weight and platelet counts, PO, QD, during 28-day cycle) plus the same AI administered during the last endocrine therapy (ET) until progressive disease (PD) or unacceptable toxicity. Main selection criteria are: (1) Men or pre- and post-menopausal women with HR+/HER2- ABC; (2) ≤1 prior regimen of chemotherapy for ABC; (3) At least 1 and up to 2 prior lines of ET (AIs or fulvestrant) for ABC (except for pts with PD in the [neo]adjuvant setting); (4) Confirmed PD during the last AI-containing regimen with secondary endocrine resistance criteria; (5) Evaluable or measurable disease. Primary endpoint is clinical benefit rate (CBR) defined as pts who achieve overall response or stable disease ≥24 weeks as per RECIST 1.1. Secondary endpoints include progression-free survival, overall response rate, time to response, duration of response, overall survival, and maximum tumor reduction. The trial uses a Simon’s two-stage minimax design. If ≥1 out of the first 6 pts of the cohort A achieve clinical benefit (CB), 8 additional pts will be recruited during stage II. At least 3 out of 12 evaluable pts with CB will be adequate to justify this strategy in further studies. Considering a drop-out rate of 10%, 14 pts will be needed to attain 80% power at nominal level of one-sided alpha of 0.025. The exploratory cohort B will be initiated if the criterion of the cohort A for continuing to the stage II is met. NCT04240106; released on January 27, 2020. MedSIR. TESARO/GSK.