Abstract 3900: Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer
Authors: Belz Jodi , Castilla Ojo Noelle , Baldwin Paige , Kumar Rajiv , van de Ven Anne , Liby Karen , Cormack Robert , Makrigiorgos Mike , Sridhar Srinivas 
Published: July 2016

Abstract
Sustained localized delivery of cancer therapeutics is a safe and effective unique option for non-metastatic cancers. Here we report a novel biodegradable implant with the capability to encapsulate therapeutics, molecular agents, or nanoparticles for local intratumoral delivery. We have successfully demonstrated in vivo the delivery of PARP inhibitor Talazoparib to treat Brca1-mutated cancers and Docetaxel to treat localized or recurring prostate cancers. This one-time intratumoral injection provides a safe vehicle for the sustained release of PARP inhibitor Talazoparib and chemotherapeutic Docetaxel in contrast to low bioavailability and toxicity associated with oral or systemic delivery.
Methods: Biodegradable implants of 1-2mm length and 0.8mm diameter were loaded with ∼50μg Talazoparib (BMN) for BRCA1-mutated breast cancer (BCa) studies and ∼500μg Docetaxel (DTX) for prostate cancer (PCa) studies. Implants were characterized using SEM and HPLC, and release studies were carried out in pH 6.0 PBS buffer at 37°C. The IC50's were determined using an MTS assay in cell lines W0069 and W780 (BCa) and PC3 (PCa). In vivo studies were carried out in Brca1 Co/Co;MMTV-Cre; p53+/− spontaneous tumored mice for BCa studies. Subcutaneous PC3 tumors were xenografted in nude mice. PCa studies were done with and without radiation. Implants were injected once intratumorally using an 18G brachytherapy needle.
Results: The release profile of the drug from the implant in buffer showed a highly sustained release for multiple weeks at therapeutically relevant doses for both DTX and BMN loaded implants. BCa cell lines W0069 and W780 were highly sensitive to BMN, most likely due to Brca1 mutation. Following a one-time intratumoral implantation of BMN, tumors reduced in size by an average of 50%, while untreated tumors increased ∼5X in size. BMN dosing appeared to be well tolerated by the mice. DTX implants proved to be an effective method for PCa treatment in vivo with no weight loss observed. The local DTX group showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days 89% survival was observed for mice treated with localized DTX implants compared with 0% in all other treatment groups. Histology samples were taken from sacrificed mice and immunohistochemistry is currently underway.
Conclusions: Sustained local release of therapeutically relevant doses of BMN and DTX were observed in vitro and in vivo. Therapeutics loaded in implants represent a novel delivery modality that is well-tolerated. Sustained release of BMN appears to amplify the therapeutic efficacy of PARP inhibition in BRCA1 mutated breast cancers and sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy. These results lay a strong foundation for the use of localized biodegradable implants for the treatment of breast and prostate cancer.
Citation Format: Jodi Belz, Noelle Castilla Ojo, Paige Baldwin, Rajiv Kumar, Anne van de Ven, Karen Liby, Robert Cormack, Mike Makrigiorgos, Srinivas Sridhar. Sustained release of PARP inhibitor Talazoparib and chemotherapeutics from biodegradable implants for treatment of breast and prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3900.