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

Abstract

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 LOH scores 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.

• Authors: Anne Patsouris, Kadija Diop, Olivier Tredan, Daniel Nenciu, Anthony Gonçalves, Monica Arnedos, Marie-Paule Sablin, Pascal Jézéquel, Marta Jimenez, Nathalie Droin, Ivan Bièche, Céline Callens, Andrea Loehr, Cécile Vicier, Catherine Guerin, Thomas Filleron, Fabrice André
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 159 Pg. 283-295 (12 2021) ISSN: 1879-0852 [Electronic] England
• PMID: 34837859 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Indoles
• rucaparib

Topics

• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Breast Neoplasms (drug therapy, genetics)
• Female
• Humans
• Indoles (therapeutic use)
• Loss of Heterozygosity
• Middle Aged
• Mutation
• Treatment Outcome