Exploring impact of mutations in non-BRCA DNA damage response (DDR) and non-DDR genes on efficacy in phase III EMBRACA study of talazoparib (TALA) in patients (pts) with germline BRCA1/2 mutated (gBRCAm) HER2-negative (HER2-) advanced breast cancer (ABC).

Abstract

1018 Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .