Impact of different sequencing strategies of talazoparib and carboplatin combination upon efficacy and toxicity in BRCA-wild type and BRCA-mutant triple-negative breast cancer models.

Abstract

586 Background: PARP inhibitors (PARPi) such as talazoparib and olaparib, have demonstrated an improvement in progression-free survival (PFS) amongst metastatic HER2-negative breast cancer patients with germline mutations in BRCA1/2 (BRCA-MUT). Clinical trials have evaluated PARPi in combination with carboplatin, but with mixed results. Earlier trials studied the combination of carboplatin and a low-dose PARPi of low potency, veliparib. The concomitant combination of carboplatin and talazoparib, a higher-potency PARPi, was also evaluated in solid tumors, using a heavily pre-treated population. Here, we perform a comparative evaluation of different sequencing strategies of talazoparib and carboplatin to determine efficacy and toxicity in BRCA-MUT and BRCA wild-type (WT) TNBC models. Methods: We used three orthotopic xenograft models in NSG (NOD scid gamma) mice, with 7-14 mice in each treatment group: MDAMB231 (BRCA-WT), HCC1806 (BRCA-WT), and MX1 (BRCA-MUT). We treated mice with carboplatin (C) (35 mg/kg intraperitoneally) in combination with talazoparib (T) (0.33 mg/kg oral gavage) using 2 dosing strategies: a) concomitant administration of C + T; and b) T first, followed by C three days later, each compared to vehicle control. We evaluated primary tumor inhibition and hematologic toxicity. Kruskal-Wallis test and Dunn’s multiple comparison test was used to assess statistical significance. Results: Using the MDAMB231 xenograft, we found the T-first approach led to a 66.7% (P < 0.0001), and the concomitant approach resulted in a 51.4% decrease in primary tumor volume, (P = 0.08), in comparison to control. In HCC1806, the T-first approach resulted in a 62.0% decrease in tumor volume (P < 0.0001), whereas the concomitant combination showed a 54.4% decrease (P = 0.002). In MX1, the T-first and concomitant approaches resulted in 72.7% (P < 0.0001) and 81.4% (P < 0.0001) decrease in tumor volume, respectively. With regards to neutrophil counts, T-first approach decreased neutrophils by 66.2% and 43.0% in MDAMB231 and HCC1806 xenografts respectively, similar to the trend with concomitant T + C: 61.4% and 38.0%. In the MX1 cohort, the T-first approach resulted in a 66.2% decrease in neutrophils (P = 0.001), and the concomitant approach led to a 77.5% decrease in neutrophils (P = 0.006). Conclusions: Our results demonstrate that the talazoparib-first approach is effective in two BRCA-WT models with no statistically significant neutropenia. While the concomitant combination approach demonstrated greater tumor inhibition in the BRCA-MUT model, this was also associated with significant neutropenia. This is suggestive that sequencing of talazoparib and carboplatin may have differential effect in BRCA-WT and BRCA-MUT tumors and may play an important role in improving efficacy in BRCA-WT tumors.