Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer

Joanne L Blum, A Douglas Laird, Jennifer K Litton, Hope S Rugo, Johannes Ettl, Sara A Hurvitz, Miguel Martin, Henri H Roché, Kyung-Hun Lee, Annabel Goodwin, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Julia F Hopkins, Lee A Albacker, Lida A Mina, Joanne L Blum, A Douglas Laird, Jennifer K Litton, Hope S Rugo, Johannes Ettl, Sara A Hurvitz, Miguel Martin, Henri H Roché, Kyung-Hun Lee, Annabel Goodwin, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Akos Czibere, Julia F Hopkins, Lee A Albacker, Lida A Mina

Abstract

Purpose: PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood.

Experimental design: Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.

Results: In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy.

Conclusions: Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.

Trial registration: ClinicalTrials.gov NCT01945775.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Tumor sequencing and concordance with germline BRCA status—evaluable ITT population. The proportion of patients with a known gBRCAmut by Central lab who have a BRCA1/2mut (defined as known or likely pathogenic variant, CNAs excluded) detected in a tumor using FoundationOne CDx. All patients showing concordant BRCA1 or BRCA2 mutational status exhibited the same mutation in tumor as originally detected in germline, as evidenced by mapping to a common Variation ID in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar) or other comparative means, with one exception (1 patient who exhibited a distinct BRCA2mut in germline and tumor). A total of 14 patients were discordant: 2 patients—same germline variants used to support enrollment were classified by the FoundationOne CDx test as pathogenicity unknown; 7 patients exhibited gBRCA deletion impacting one or multiple exons and were hence mapped to Rearrangement category. These patients exhibited alterations classified as pathogenic BRCA CNAs by FoundationOne CDx in the corresponding BRCA genes; 2 patients—gBRCA2mut, tBRCA1mut; 1 patient—gBRCA1mut, tBRCA2mut; 2 patients—no tBRCA variant detected.
Figure 2.
Figure 2.
Kaplan–Meier curves for duration of radiographic PFS by IRF assessment—ITT population evaluable for PFS and gLOH. Chemo, chemotherapy; cum, cumulative; ev, events; REF, reference; TALA, talazoparib. aHigher and lower indicate that gLOH is above or below the median, respectively. HR is based on unstratified Cox regression model and is relative to talazoparib gLOH < median or chemotherapy gLOH < median with <1 favoring higher gLOH.

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Source: PubMed

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