Abstract P1-14-03: ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial
Authors: Telli ML , Turner NC , Mailliez A , Ettl J , Grischke E-M , Mina LA , Balmaña J , Hurvitz SA , Wardley AM , Fasching PA , Tudor C , Nguyen L , Hannah AL , Robson ME , Rugo HS 
Published: February 2018

Abstract
Background: Talazoparib (TALA) is a dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor that traps PARP on DNA. Efficacy results of this phase 2 trial were previously presented (Turner et al, ASCO 2017, abstract 1007). This study included sparse pharmacokinetic (PK) sampling for patients through cycle 4 of therapy. Exploratory analyses included assessment of exposure versus parameters of efficacy and safety.
Methods: ABRAZO (NCT02034916) was a parallel-cohort, open-label phase 2 study of TALA (1 mg/d) following (i) platinum-based therapy (cohort 1) or (ii) ≥3 platinum-free cytotoxic-based regimens (cohort 2) in patients with locally advanced or metastatic breast cancer and germline BRCA1/2 mutation. Sparse PK sampling was performed on day 1 of cycles 1-4, consisting of a predose sample collected ≤60 minutes prior to dosing and 2 postdose samples collected ≥30 minutes after dosing (time of food ingestion prior to the dose was collected). The collection times of the 2 postdose samples were separated by ≥2 hours. Efficacy parameters included radiographic progression-free survival (rPFS) by central review and objective response rate (ORR). Safety parameters included incidence of overall adverse events (AEs) and grade ≥3 AEs. Individual AUCs (area under concentration-time curves) for exposure-response analyses were predicted by population PK analyses.
Results: Patients were divided into AUC tertiles: low (median, 109.0 ng*hr/mL; n=27), intermediate (median, 170.8 ng*hr/mL; n=27), and high (median, 219.2 ng*hr/mL; n=27). Median rPFS was 5.3 months (95% confidence interval [CI], 3.1, 8.3) in the lowest AUC tertile, 5.6 months (95% CI, 3.7, 8.4) in the intermediate AUC tertile, and 5.3 months (95% CI, 3.9, 5.6) in the highest AUC tertile. The ORR was 22.2% (95% CI, 8.6, 42.3) in the lowest AUC tertile, 25.9% (95% CI, 11.1, 46.3) in the intermediate AUC tertile, and 37.0% (95% CI, 19.4, 57.6) in the highest AUC tertile. AEs of any grade were reported in 11 patients (40.7%) in the lowest AUC tertile, 21 patients (77.8%) in the intermediate AUC tertile, and 22 patients (81.5%) in the highest AUC tertile. Grade ≥3 AEs were reported in 8 patients (29.6%) in the lowest AUC tertile and in 18 patients (66.7%) in the intermediate and highest AUC tertiles. The most common AEs in all 3 exposure tertiles were anemia, thrombocytopenia, and neutropenia.
Conclusions: Median rPFS did not change with increasing systemic exposure. There may be a trend to higher ORR in patients with highest systemic exposure. A larger percentage of patients experienced AEs with elevated systemic exposure. Increased response rates with greater exposure does not translate to improved rPFS. These results should be interpreted with caution due to the low patient numbers in each cohort.
Citation Format: Telli ML, Turner NC, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Hurvitz SA, Wardley AM, Fasching PA, Tudor C, Nguyen L, Hannah AL, Robson ME, Rugo HS. ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-03.