# Niraparib Plus Aromatase Inhibitors for Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with a Germline BRCA Mutation

## TL;DR

This study shows that combining niraparib and aromatase inhibitors may be an effective treatment for advanced breast cancer in patients with BRCA mutations.

## Contribution

The study demonstrates the potential of combining PARP inhibitors with aromatase inhibitors in BRCA-mutated breast cancer patients.

## Key findings

- The clinical benefit rate was 46.2% in patients with BRCA mutations.
- Median progression-free survival was 5.5 months and median overall survival was 18.1 months.
- The treatment had a manageable safety profile consistent with known drug toxicities.

## Abstract

This study focuses on finding better treatments for women with advanced breast cancer who have certain genetic mutations. BRCA proteins are essential for repairing damaged DNA, and when these proteins are defective, it can lead to breast cancer. Women with BRCA mutations are at a higher risk of developing this cancer. The LUZERN study explored the combination of two drugs—niraparib, a PARP inhibitor, and aromatase inhibitors—to treat women with HR-positive/HER2-negative advanced breast cancer, particularly those with BRCA mutations or other DNA repair issues. The main goal was to see if this combination could provide a clinical benefit, meaning if it helped shrink the tumors or stabilize the disease for at least 24 weeks. This study found promising results, suggesting that this combination therapy might be an effective treatment for these patients, although more research is needed to confirm its benefits. The findings could help improve treatment strategies for patients with specific genetic profiles.

Background: Niraparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor with promising activity for patients with advanced breast cancer harboring germline BRCA1/2 mutations. Methods: LUZERN (NCT04240106) was a multicenter, open-label, Simon’s two-stage, phase II clinical trial evaluating the efficacy and safety of niraparib with aromatase inhibitors (AIs) for patients with HR-positive/HER2-negative advanced breast cancer with either a germline BRCA1/2 mutation (cohort A) or germline BRCA1/2 wild-type and homologous recombination deficiency (exploratory cohort B). Eligible patients received ≤1 line of chemotherapy and 1–2 prior lines of endocrine therapy for advanced disease with secondary resistance to the last AI-based regimen. Patients received niraparib (300 mg or 200 mg) plus an AI. The primary endpoint was the clinical benefit rate (CBR) in cohort A. Results: Between June 2020 and November 2022, 14 patients were enrolled in cohort A (n = 6 for stage I, n = 8 for stage II) and no patients were enrolled in cohort B. One patient was excluded from the efficacy analysis due to no prior AI treatment. Nearly all patients (92.9%) previously received a cyclin-dependent kinase 4/6 inhibitor, but no patients had received prior platinum-based chemotherapy. Median follow-up was 16.7 months (range: 13.2–18.2). The CBR was 46.2% (95% CI: 19.2–74.9), meeting the primary endpoint. Median progression-free survival was 5.5 months (95% CI: 1.9–8.5), and median overall survival was 18.1 months (95% CI: 9.7–NE). The safety profile was consistent with the known toxicity of both drugs. Conclusions: Niraparib combined with an AI has encouraging antitumor activity and a manageable safety profile in patients with AI-resistant HR-positive/HER2-negative advanced breast cancer with germline BRCA1/2 mutations.