KEY TAKEAWAYS
- The phase III EMBRACA trial compared talazoparib against chemotherapy for germline BRCA1/2 mutations.
- 96.1% of the evaluable intent-to-treat group had a tBRCA mutation; tBRCA and gBRCA mutational status were strongly correlated.
- Despite population variability and low patient numbers in subgroups, BRCA LOH and DDR gene mutational burden remain relevant.
- More significant patient cohorts are needed to investigate PARP inhibitor response in germline BRCA1/2 mutant individuals.
Tumors with mutations in the germline breast cancer susceptibility genes (gBRCA) 1 and 2 respond well to PARP inhibitors (PARPi); however, the mechanisms that influence responsiveness to PARPi are poorly understood. In the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy, tumor tissue from patients with gBRCA1/2 mutations was sequenced using FoundationOne CDx. There was high concordance (95.3% or higher) between tBRCA and gBRCA mutational status, with 96.1% (296/308) of the evaluable intent-to-treat group having at least ≥ 1tBRCA mutation.
There was no correlation between talazoparib efficacy and genetic/genomic characteristics such as BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, or tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)]. Results were tempered by population heterogeneity and low patient numbers in some subgroups, but overall, BRCA LOH status, DDR gene mutational load, and gLOH were not linked with talazoparib efficacy. Further research is needed with more extensive samples of patients.
Source: https://pubmed.ncbi.nlm.nih.gov/35091441/
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT01945775
Blum JL, Laird AD, Litton JK, Rugo HS, Ettl J, Hurvitz SA, Martin M, Roché HH, Lee KH, Goodwin A, Chen Y, Lanzalone S, Chelliserry J, Czibere A, Hopkins JF, Albacker LA, Mina LA. Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer. Clin Cancer Res. 2022 Apr 1;28(7):1383-1390. doi: 10.1158/1078-0432.CCR-21-2080. PMID: 35091441; PMCID: PMC9365365.
