Abstract C54: Combination of PARP inhibitor talazoparib with etirinotecan pegol exhibits synergistic anti-tumor effect in non-BRCA preclinical cancer models
Authors: Feng Ying , Shen Yuqiao (Jerry) , Post Leonard E. , Doberstein Steve , Charych Deborah , Hoch Ute 
Published: May 2016

Abstract
Introduction: Talazoparib (BMN 673) is a highly potent and specific PARP1/2 inhibitor (PARPi) that has demonstrated significant clinical activity in patients with germline BRCA mutation ovarian and breast cancer, as well as in patients with small cell lung cancer. Non-clinically, combination of PARPi, including talazoparib, with Topoisomerase 1 (Top1) inhibitors, such as irinotecan, has shown synergy in BRCA1 mutant MX-1 model (Shen et al. 2013; Hoch et al., NCI-AACR-EORTC 2014). Etirinotecan pegol (NKTR-102, pegylated irinotecan) is a long-acting Top1 inhibitor, designed to provide extended drug exposure to the tumor. In preclinical models, NKTR-102 has improved efficacy and tolerability over irinotecan. We therefore hypothesized that the combination of talazoparib with NKTR-102 would be well tolerated and harness the full synergistic potential of combined Top1 and PARP inhibition.
Method: In tolerability studies, three dose levels of talazoparib (0.1, 0.2 and 0.3 mg/kg, QDx14) given with NKTR-102 (10 and 50 mg/kg irinotecan-equivalent dose, iv. Q7Dx2), or irinotecan (10, 30 and 60 mg/kg, ip, Q7Dx2) were evaluated in non-tumor-bearing nude mice (Balb/c, n = 4 per group). In efficacy studies, multiple dose levels of a single agent (i.e., talazoparib, NKTR-102, or irinotecan) as well as corresponding dose combinations were evaluated in NCI-H1048 and HT-29 xenograft tumors with wildtype BRCA status (n = 8-10 per group). Tumor volume and body weight were measured twice weekly.
Results: For talazoparib and NKTR-102, all combination doses were tolerated, the maximum mean body weight loss reached 6.2% in the high dose group (0.3 mg/kg talazoparib plus 50 mg/kg NKTR-102). For talazoparib and irinotecan, MTD was observed at 0.2 mg/kg BMN 673 plus 30 mg/kg irinotecan. In efficacy studies, single-agent NKTR-102 had dose-dependent anti-tumor activity against NCI-H1048 tumor, while talazoparib showed limited activity with QDx14 dosing schedule. Combination of talazoparib (0.2 or 0.3 mg/kg, QDx14) with NKTR-102 (10 mg/kg, Day 1) exhibited significantly greater anti-tumor effect than either single agent alone. In contrast, combination of talazoparib (0.2 mg/kg, QDx14) with irinotecan (30 mg/kg, Day 1) only had moderate combination effect in the NCI-H1048 model. In HT-29 model, additive anti-tumor effect was also observed for talazoparib + NKTR-102, but not for talazoparib + irinotecan under the same experimental condition.
Conclusion: Our data indicate that the combination of NKTR-102 and talazoparib is better tolerated than that of irinotecan and talazoparib, and results in stronger combination anti-tumor activity. The results support potential development of the combination in human studies.
Citation Format: Ying Feng, Yuqiao (Jerry) Shen, Leonard E. Post, Steve Doberstein, Deborah Charych, Ute Hoch. Combination of PARP inhibitor talazoparib with etirinotecan pegol exhibits synergistic anti-tumor effect in non-BRCA preclinical cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C54.