In vivo synergism between PARP-inhibitor olaparib and HSP90-inhibitor AT13387 in high grade serous ovarian cancer patient derived xenografts.

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Abstract
E17045 Background: Our previous in vitro work has demonstrated that HSP90-inhibition suppresses homologous recombination (HR) DNA repair and sensitizes HR-proficient ovarian cancer lines to platinum and PARP-inhibitors(PARPis). In this study, we evaluated the combination of PARPi olaparib and the HSP90-inhibitor AT13387 in vivo, in a panel of molecularly characterized high grade serous ovarian cancer patient derived xenograft (PDX) mouse models. Methods: PDX models were established from fresh human ascites samples from patients with either newly diagnosed or recurrent ovarian cancer through an IRB approved protocol. High grade serous ovarian cancer (HGSOC) cells were implanted intraperitoneally into immunocompromised mice and these models were luciferized thereby providing the ability to follow tumor growth and response to therapy by non-invasive bioluminescent imaging technology. Response to therapy was also evaluated by CA125 levels. Olaparib and AT13387 combination tolerability studies were performed prior to the initiation of combination efficacy studies. Results: Tolerability studies demonstrated that doses of olaparib up to 100mg/kg po daily x 3 weeks and AT13387 up to 45mg/kg po for 2 days on / 5 days off x 3 weeks (Days 1, 2, 8, 9, 15, 16) were well tolerated without weight loss in the mice or gross changes in normal tissue histology. Preclinical evaluation of efficacy of treatments (vehicle vs AT13387 vs olaparib vs olaparib plus AT13387) was subsequently performed in one mouse per treatment arm in each PDX model. The combination of AT13387 and olaparib inhibited tumor growth in 8 of 14 PDX models including one BRCA1-mutated/PARPi-resistant model, 2 models with CDKN2A loss and 1 model with CCNE1 amplification. Of these 8 models, 4 were clinically platinum resistant, 2 platinum sensitive, and 2 unknown. Of 11 models with measurable CA125, CA125 responses were seen in 7 models. Pharmacodynamic studies are ongoing. Conclusions: PARPi olaparib and HSP90i AT13387 exhibit synergistic activity in vivo, in a number of high grade serous ovarian cancer PDX models, including HR proficient models. A phase I clinical trial of this combination in HGSOC is planned.