Genetic/Genomic Mutations Exhibit No Association With Talazoparib Efficacy Among Patients With HER2-Negative BRCA1/2

Genetic/genomic attributes demonstrated no association with talazoparib efficacy among patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer and germline breast cancer susceptibility genes 1 and 2 mutations (gBRCA 1/2), according to results from a retrospective analysis of tumor tissue samples from the phase 3 EMBRACA study.

“While the efficacy of the PARP inhibitor talazoparib has been demonstrated in patients with (gBRCA1/2)-mutated HER2-negative locally advanced or metastatic breast cancer, less is known about tumor-related factors that might influence response to talazoparib," explained Joanne L Blum, MD, Baylor Charles A. Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, Texas, and colleagues.

The open-label, international, phase 3 EMBRACA trial enrolled 431 patients with advanced breast cancer and a gBRCA1/2 mutation, randomized on a 2:1 basis to either 1 mg talazoparib once daily (n = 287), or standard single-agent therapy  of either capecitabine, eribulin, gemcitabine, or vinorelbine (n = 144). The trial results found that talazoparib conveyed a significant benefit in progression-free survival, compared to standard chemotherapy, in this patient population.

Of the 308 evaluable patients in the EMBRACA study, 296 (96.1%) displayed ≥1 tumor BRCA (tBRCA) mutation, and nearly the same number (95.3%) of patients experienced cooccurrence of tBRCA and gBRCA mutational status. Genetic/genomic characteristics such as BRCA loss-of-heterozygosity (LOH) status (82.6%), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency (HRD) assessed by genomic LOH (gLOH) exhibited no association with talazoparib clinical benefit.

The subgroup of patients with triple-negative breast cancer (TNBC) appeared to be a potential outlier, though the authors noted the high interpatient variability and the small size of the subgroup as limitations in assessing the significance of this exception.

“Taken together, these results showing high concordance between gBRCA and tBRCA mutations, high prevalence of BRCA LOH, and overall lack of association of BRCA LOH or HRD with outcomes in patients with gBRCA mutations,” Dr Blum and colleagues concluded, adding, “Further research is warranted and will be important in identifying patients in the clinic who may maximally benefit from talazoparib treatment.”

Sources:                                       

Blum JL, Laird AD, Litton JK, et al. Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer. Clin Cancer Res. 2022;28(7):1383-1390. doi:10.1158/1078-0432.CCR-21-2080

Litton LK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018; 379:753-763. doi:10.1056/NEJMoa1802905.