Abstract 1994: Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA deficient ovarian cancer
Authors: Yang Shicheng , Brown Needa , Campbell Abigail L. , Aggarwal Kushi , Dinulescu Daniela M. , Sridhar Srinivas 
Published: April 2023

Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors, such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ over 25 days directly into the peritoneal cavity (i.p.) to treat BRCA-mutated metastatic ovarian cancer (mOC).

Methods: InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The detailed structure of InCeT-TLZ was checked by scanning electron microscopy. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally metastatic ovarian cancer model. Treatment started 7 days post tumor inoculation. All mice were monitored by IVIS imaging once a week to confirm and track tumor growth. On day 8, mice with tumors (4-5 mm in diameter) were divided into 4 groups: PBS i.p. injection (50 μl, three times a week), empty implant i.p. implantation (2.5 mm, every 25 days), TLZ i.p. injection (0.33 mg/kg of TLZ by i.p. injection three times a week), and InCeT-TLZ i.p. implantation (2.5 mm, equal to a total amount of 10 i.p. injection doses, every 25 days). Body weight was recorded three times a week as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight.

Results and Conclusion: The drug-loaded PLGA implant was developed for the sustained and local delivery of TLZ to treat high-grade serous ovarian cancer with a loading efficiency of 26.75 μg/mm. Implants can be easily placed into the peritoneal cavity of patients or animals with an 18-gauge clinical needle. The extended survival in InCeT-TLZ treated mice compared to the TLZ injection group indicated that the slow release of TLZ maximizes PARP inhibitor therapy in the peritoneal cavity for disseminated cancer treatment. Decrease in ascites formation within the intraperitoneal cavity of the InCeT-TLZ group suggests a promising treatment for ovarian cancer-associated ascites and disease progression. Histopathology following peritoneal InCeT-TLZ implantation showed no toxicity in any surrounding organs at risk. This approach would offer new sustained therapy options for substantially enhancing the therapeutic window, increasing cure rates, reducing mortality and suffering, and offering major enhancements in quality of life for the thousands of women diagnosed with OC yearly.

Citation Format: Shicheng Yang, Needa Brown, Abigail L. Campbell, Kushi Aggarwal, Daniela M. Dinulescu, Srinivas Sridhar. Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA deficient ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1994.