Localized Delivery Of The Parp Inhibitor Talazoparib For Chemoprevention Of Breast Cancer

Mutations in BRCA genes are the leading cause of hereditary breast cancer and dramatically increase the lifetime risk of developing breast cancer. Anti-estrogen drugs are approved to reduce the risk of developing invasive breast cancer, but they are not effective for women with germline BRCA mutations and are limited by undesirable toxicities. Radical mastectomy provides a surgical option for high-risk patients for cancer prevention, but the physical and emotional challenges of such a radical surgery confirm that alternative approaches are needed. Our goal is to develop novel chemopreventive agents that are effective and safe for BRCA carriers. PARP inhibitors are effective for treating BRCA-mutated breast cancer patients, and we have shown that these drugs significantly delayed tumor development in BRCA-deficient mice. Here, we developed a novel implantable formulation of the PARP inhibitor Talazoparib for local delivery and thus provide a new therapeutic strategy for prevention of breast cancer. Talazoparib (TLZ) was encapsulated into spacer implants (InCeT-TLZ, 25 μg/mm) and is released in a linear manner from the implant over 30 days. When BRCA-deficient breast cancer cells were treated with the InCeT-TLZ implant in vitro, 83.1%±1.4% of the cells were dead after 7 days of treatment. To determine in vivo efficacy, age-matched BRCACo/Co;MMTV-Cre;p53+/-mice were randomized into three groups: empty spacers (2 mm), oral TLZ (50 μg given over 4 weeks), and InCeT-TLZ (50 μg, 2 mm). Using brachytherapy needles, spacers were implanted into mammary glands of the BRCA-deficient mice at 12, 16 and 20 weeks of age, before tumors had developed, and tissues were harvested 4 weeks after implantation. InCeT-TLZ significantly (p Citation Format: Di Zhang, Bijay Singh, Jessica Moerland, Owen Mitchell, Lizbeth Lockwood, Sarah Carapellucci, Srinivas Sridhar, Karen Liby. Localized delivery of the PARP inhibitor Talazoparib for chemoprevention of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 12.