Olaparib is an oral inhibitor of the Poly-(ADP-ribose)-polymerases (PARP-1, -2 and -3), and has demonstrated clinical activity in trials of patients with BRCA-deficient tumors. The BRCA1 and BRCA2 proteins are both important for the repair of DNA double strand breaks (DSBs) by homologous recombination repair (HRR) and sensitivity to olaparib has further been shown preclinically to extend to other DNA DSB repair factor deficiencies, including those in the ataxia telangiectasia mutated (ATM) protein.

We have demonstrated that a high proportion of gastric cancer (GC) cell lines (∼50%) are responsive (IC50 <500 nM) to single agent olaparib and that characterization of their DNA repair status reveals that, as in breast and ovarian cancer, HRR deficiencies (HRD) can account at least in part for this. However, unlike breast and ovarian cancer cell lines, there is no strong correlation with platinum sensitivity, suggesting alternative drivers of response in the GC panel to HRD. Here, we demonstrate that low levels of ATM protein expression correlate with sensitivity of GC cell lines to olaparib, and moreover can be observed in approximately 15-20% of clinical gastric cancer samples when evaluated using ATM immunohistochemistry (IHC).

Based on these data, a Phase II GC trial has been carried out that enriches for patients with tumors having low or undetectable ATM IHC scores (H-score equivalent less than or equal to 10). Data from this clinical trial confirm activity (overall survival [OS] benefit HR=0.56, 95% CI: 0.35-0.87; P=0.010) in the overall population, which includes ATM tumor positive patients, and importantly, a substantially better OS benefit in the ATM-negative population (HR=0.35, 95% CI: 0.17-0.71; P=0.003). Together, these data provide an important example of a PARP inhibitor demonstrating both preclinical and clinical activity in a well defined but non-BRCA DNA repair deficient background.

Citation Format: Darren Hodgson, Helen Mason, Lenka Oplustilova, Chris Harbron, Xiaolu Yin, Seock-Ah Im, Helen Jones, Lai Zhongwu, Brian Dougherty, Matthew McLoughlin, James Bradford, Andrew Dickinson, Anitra Fielding, Jane Robertson, Woo-Ho Kim, Chris Womack, Yi Gu, Yung-Jue Bang, Alan Lau, J. Carl Barrett, Mark J. O'Connor. Activity of the PARP inhibitor olaparib in ATM-deficient gastric cancer: from preclinical models to the clinic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2398. doi:10.1158/1538-7445.AM2014-2398