3546 - Preclinical efficacy of TTFields and PARP inhibitors in ovarian cancer models

Y. Berckmans¹, H. Ene², K. Ben-Meir², A. Martinez-Conde², R. Monin², B. Van den Ende¹, S. Van Mechelen¹, R. Frechtel-Gerzi², H. Gabay², E. Dor-On², H. Mumblat², A. Haber², M. Giladi², U. Weinberg², Y. Palti², I. Vergote³, and A. Coosemans¹; ¹Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium, ²Novocure Ltd, Haifa, Israel, ³Department of Gynecology and Obstetrics, Gynecologic Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium

Purpose/Objective(s): Ovarian cancer is the leading cause of mortality among gynecological malignancies. Selected cases of advanced epithelial ovarian cancer are treated with standard-of-care poly (ADP-ribose) polymerase inhibitors (PARPi). Tumors that are homologous recombination deficient (HRD), including mutations in the Fanconi Anemia (FA) BRCA pathway, exhibit sensitivity to PARPi. Unfortunately, about 75% of ovarian tumors are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recent research in various cancer types showed that TTFields can induce an HRD-like state. The current study aims to investigate efficacy of TTFields applied together with PARPi in preclinical models of ovarian cancer. Materials/

Methods: Human ovarian cancer cells A2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various concentrations of PARPi olaparib or niraparib. At treatment end, cell count, colony formation and ?H2AX foci formation (indicative of DNA damage) were measured, and the overall effect was calculated (by multiplying effects on cell count with colony formation). TTFields-treated cells were evaluated for the expression of proteins from the FA-BRCA pathway. In vivo, 6-8-week-old C57BL/6 mice were inoculated intraperitoneally with ID8-fLuc (HRP) ovarian cancer cells. Seven days post inoculation, mice were treated with sham-vehicle, TTFields, olaparib (50 mg/kg), or TTFields with olaparib over a four-week period. Tumor growth was analyzed at treatment cessation using bioluminescent imaging, and the mice were further evaluated for overall survival.
Results: Interaction of TTFields with PARPi demonstrated additivity in the HRD OVCAR-3 cells, moderate synergy in the platinum-resistant A2780cis cells, and highest synergy in the HRP A2780 cells. Downregulation of various FA-BRCA protein was seen after TTFields treatment, with consequent increased DNA damage following the application of TTFields together with the PARPi. TTFields with olaparib co-treatment resulted in reduced tumor volume in ovarian tumor-bearing mice and a survival benefit relative to control-treated mice and to mice treated with the monotherapies.
Conclusion: The data suggest potential advantages for concomitant treatment with TTFields and PARPi in ovarian cancer, even in HRP and platinum-resistant cells, which may be attributed to the HRD-like state induced by TTFields.