Abstract
Talazoparib, a potent PARP inhibitor (PARPi), induces synthetic lethality in BRCA-deficient cancers making it an attractive candidate for ovarian cancer treatment. However, its potency lends itself to side effects associated more closely with traditional chemotherapeutics than other clinically approved PARPi's. We sought to formulate Talazoparib in a nanoparticle delivery system such that the drug could be administered intraperitoneally, localizing the entire dose at the disease site, to increase therapeutic efficacy and minimize toxicity. NanoTalazoparib was formulated and characterized and found to have a mean diameter of 70 nm and a neutral surface charge. Talazoparib and NanoTalazoparib were tested on a panel of murine tubal and human HGSOC cell lines and dose response compared to the first clinically approved PARPi, Olaparib. Dose response data indicated all cell lines were more sensitive to Talazoparib and NanoTalazoparib than Olaparib and all lines showed the same sensitivity to nanoformulations as free drugs. The human cell lines had various BRCA mutations and deletions, as well as a homologous recombination proficient (HRP) line, however, the HRP line was more sensitive to treatment than some HRD lines. Therapeutic efficacy was tested in vivo in a murine cancer model that mimics disseminated peritoneal disease. NanoTalazoparib 3X weekly for 8 weeks did not shrink tumors but resulted in tumor growth inhibition of 64% while an equivalent dose of oral Talazoparib only resulted in 34% growth inhibition. NanoTalazoparib suppressed the average volume of ascites at the study endpoint by 3.45 times more than oral Talazoparib. H&E staining of the tissues indicated no significant toxicity to the organs of the mononuclear phagocyte system. These results indicate that NanoTalazoparib can be used to localize PARPi therapy to the peritoneal cavity for disseminated late stage ovarian cancer treatment. Our data suggests that NanoTalazoparib could be utilized to delay the formation of tumor ascites for women with HR-deficient disease. While NanoTalazoparib did not effectively treat the disseminated disease at this dose, it may have clinical utility, either in combination with other therapies or as a maintenance therapy. Preclinical data indicates PARP inhibitors potentiate damage when combined with other cytotoxic treatments, however, in the clinic this has resulted in enhanced toxicity, forcing dose reduction and delay. The IP administration of NanoTalazoparib may provide a route to bypass some of the toxicities that have plagued combination treatments.
Supported in part by Rivkin Foundation and CDMRP Ovarian Cancer Research Program
Citation Format: Paige Baldwin, Anders Ohman, Jamie Medina, Daniela Dinulescu, Srinivas Sridhar. NANOFORMULATION OF TALAZOPARIB SUPPRESSES TUMOR GROWTH AND ASCITES IN A DISSEMINATED CANCER MODEL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-087.
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