Abstract A063: PARPi and ATRi (AZD6738) in BRCA associated PDAC patient derived xenograft model
Authors: Golan Talia , Atias Dikla , Stossel Chani , Gurevich Maria Raitses , Glick Yulia Gurmon , Halparin Sharon , Talmoud Elina Haimov , Amison Nora , Beller Tamar , Berger Raanan 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease, with the majority of patients diagnosed at an advanced stage. Comprehensive genomic analysis identified the homologous recombination deficiency (HRD) subgroup which is predominantly enriched in patients harboring germline BRCA1/2 mutations (glBRCA) and presents ~7% and up to 15% in selected high-risk populations. Tumors with HRD are susceptible to DNA-damaging agents and PARP inhibition. However, not all patients demonstrate a similar response, and a spectrum is observed. We analyzed the clinical outcome of ninety-one glBRCA PDAC patients treated at Sheba Medical Center. We identify three main subgroups of response spanning from ~25% patients refractory to first line platinum agents and ~9% patients with durable long-term response with no evidence of disease for over three years. The majority of the patients display a prolonged response to platinum and PARPi maintenance (&gt;24 months) followed by acquired resistance. ATR, a central mediator in DDR, is activated by multiple DNA damage events. Activated ATR induces cell-cycle arrest and facilitates DNA repair. Inhibition of ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA-damaging agents. Therefore, we propose combinational therapy of PARPi with ATRi. This combination treatment is expected to enhance response to PARPi in BRCA-mutated PDAC patients naïve to treatment and might extend efficacy. We generated unique patient derived xenograft (PDX) models (n=25) at distinct clinical scenarios - from naïve to treatment tissue and at clinical resistance. In-vivo efficacy to platinum agents and PARPi demonstrates that these models recapitulate the specific clinical spectrum of response. However, accumulating resistance emerges and additional therapies need to be investigated. Furthermore, we have generated an in-vivo resistant paired models from an initially platinum sensitive BRCA-PDXs, mimicking the patient clinical scenario from sensitivity to resistance. PARP and ATR combined inhibition was assessed in a PDX model generated from a glBRCAmut PDAC patient, naïve to platinum/PARPi treatment. PDX were randomized to the following groups: 1. vehicle control; 2. PARPi olaparib AZD2281 (100 mg/kg, 5 days a week IP); 3. ATRi AZD6738 (25 mg/kg, 5 days a week; PO); 4. ATRi + PARPi combination. PARPi treatment attenuated tumor growth for 42 days followed by re-growth. A significant difference in tumor growth was obtained with the combined PARPi and ATRi treatment (p&lt;0.05). Experiment is ongoing currently on day 84 and we intend to proceed while tolerated or until resistance will develop. Our preliminary in-vivo results suggest that the combinatorial treatment of PARPi and ATRi may delay resistance to single agent PARPi. This extensive preclinical and clinical collection of BRCA associated PDAC, enables further understanding and investigation of this unique subtype in aim to develop alternative treatments to overcome resistance.
Citation Format: Talia Golan, Dikla Atias, Chani Stossel, Maria Raitses Gurevich, Yulia Gurmon Glick, Sharon Halparin, Elina Haimov Talmoud, Nora Amison, Tamar Beller, Raanan Berger. PARPi and ATRi (AZD6738) in BRCA associated PDAC patient derived xenograft model [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A063.