Rucaparib in patients presenting a metastatic breast cancer with homologous recombination deficiency, without germline BRCA1/2 mutation

Background: Breast cancer may present genomic alterations leading to homologous recombination deficiency (HRD). PARP inhibitors have proven their efficacy in patients with HER2-negative (HER2-) metastatic breast cancer (mBC) harbouring germline (g) BRCA1/2 mutations in 3 phases III trials. The single-arm phase II RUBY trial included 42 patients, 40 of whom received at least one dose of rucaparib. RUBY study assessed the efficacy of rucaparib in HER2-mBC with either high genomic loss of heterozygosity (LOH) score or non-germline BRCA1/2 mutation. Patients and methods: The primary objective was the clinical benefit rate (CBR), and the study was powered to see 20% CBR using a 2-stage Simon design. Results: The primary-end point was not reached with a CBR of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (12 and 28.5 months). Whole-genome analysis was performed on 24 samples, including 5 patients who presented a clinical benefit from rucaparib. HRDetect tended to be associated with response to rucaparib, without reaching statistical significance (median HRDetect responders versus non-responders: 0.465 versus 0.040; p = 0.2135). Finally, 220 of 711 patients with mBC screened for LOH upstream from RUBY presented a high LOH score associated with a higher likelihood of death (hazard ratio = 1.39; 95% CI: 1.11-1.75; p = 0.005). Conclusion: Our data suggest that a small subset of patients with high LOHscores without germline BRCA1/2 mutation could derive benefit from PARP inhibitors. However, the RUBY study underlines the need to develop additional biomarkers to identify selectively potential responders. (C) 2021 The Authors. Published by Elsevier Ltd.

Automated summary

The RUBY study evaluated the efficacy of rucaparib in HER2-negative metastatic breast cancer patients, indicating that some patients without germline BRCA1/2 mutation could benefit from PARP inhibitors. However, additional biomarkers are needed to selectively identify potential responders.