Abstract CT072: Exploration of impact of tumor BRCA zygosity and genomic loss-of-heterozygosity (gLOH) on efficacy in Phase 3 EMBRACA study of talazoparib in patients (pts) with HER2-negative (HER2−) advanced breast cancer (ABC) and a germline BRCA1/2 (gBRCA1/2) mutation
Authors: Litton Jennifer K. , Laird A. Douglas , Rugo Hope S. , Ettl Johannes , Hurvitz Sara A. , Martin Miguel , Roché Henri , Im Young-Hyuck , Goodwin Annabel , Blum Joanne L. , Eiermann Wolfgang , Chen Ying , Lanzalone Silvana , Chelliserry Jijumon , Czibere Akos , Albacker Lee A. , Frampton Garrett M. , Mina Lida A. 
Published: September 2020

Background: Loss-of-function mutations in genes encoding components of the homologous recombination machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In EMBRACA, the PARP inhibitor talazoparib (TALA) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P &lt; 0.001) vs physician's choice of chemotherapy (PCT) in pts with HER2− ABC and a gBRCA1/2 mutation.

Methods: Baseline tumor tissue (primary or metastatic sites) from 308 pts (71%) in the intent-to-treat population was sequenced using the FoundationOne CDx NGS panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Additional exploratory computational analyses pertinent to homologous recombination deficiency were performed, including somatic-germline-zygosity (SGZ) and gLOH assessments.

Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with BRCA1 and BRCA2 mutations mainly mutually exclusive (4/308 [1%] pts had both BRCA1 and BRCA2 mutations). Of 12 pts with no apparent BRCA mutations, 7 exhibited tumor BRCA copy number alterations deemed pathogenic and 2 had BRCA single-nucleotide variants deemed of unknown pathogenicity. 195/236 (83%) BRCA-mutant (BRCAm) pts evaluable for BRCA LOH status were predicted to exhibit BRCA LOH by SGZ analysis. The potential impact of tumor BRCA mutational zygosity on PFS was explored in the TALA arm calculating HR by Cox proportional hazards model, comparing 122 pts with BRCA LOH with 27 pts without BRCA LOH. This analysis demonstrated no difference in PFS [HR (95% CI): 1.152 (0.680-1.951); P = 0.597)]. gLOH scores were variable, but mostly high: median (range), 21.8% (0.0, 52.7) and 20.5% (0.2, 40.5) for TALA and PCT arms, respectively. The potential association of gLOH scores with selected measures of efficacy was explored. Within both arms gLOH was similar in those pts achieving vs pts not achieving clinical benefit as defined by complete response, partial response, or stable disease ≥24 wks per RECIST v.1.1 as determined by investigator (P = 0.976 and 0.492, respectively, using 2-tailed t-test). In both arms, pts with gLOH ≥ median vs gLOH &lt; median exhibited similar PFS: HR (95% CI) 1.247 (0.828-1.879) for TALA; 1.238 (0.693-2.211) for PCT, with HR &lt;1 favoring gLOH ≥ median.

Conclusions: Selection based on gBRCA mutational status is appropriate to identify HER2− ABC pts with potential for clinical benefit with PARP inhibitors, with tumor BRCA zygosity and gLOH not impacting outcome (within the gBRCAm subset). Additional exploratory correlative analyses are ongoing and will be reported.

Citation Format: Jennifer K. Litton, A. Douglas Laird, Hope S. Rugo, Johannes Ettl, Sara A. Hurvitz, Miguel Martin, Henri Roché, Young-Hyuck Im, Annabel Goodwin, Joanne L. Blum, Wolfgang Eiermann, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Lee A. Albacker, Garrett M. Frampton, Lida A. Mina. Exploration of impact of tumor BRCA zygosity and genomic loss-of-heterozygosity (gLOH) on efficacy in Phase 3 EMBRACA study of talazoparib in patients (pts) with HER2-negative (HER2−) advanced breast cancer (ABC) and a germline BRCA1/2 (gBRCA1/2) mutation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT072.