Abstract C75: Rucaparib (CO-338) accumulation and persistence of PARP inhibition in vitro and in vivo and efficacy of intermittent vs continuous schedules

• Published in: Molecular cancer therapeutics Vol. 12; no. 11_Supplement; p. C75
• Main Authors: Murray, James C., Thomas, Huw D., Berry, Philip, Kyle, Suzanne, Jones, Christopher, Plummer, Ruth, Boddy, Alan V., Curtin, Nicola J.
• Format: Journal Article
• Language: English
• Published: 01.11.2013
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-C75

Abstract Background: Preclinical studies show that both duration and extent of PARP inhibition is critical for synthetically lethality in tumors with defects in homologous recombination repair (HRR). Rucaparib is undergoing clinical evaluation in HRR-defective tumors. Our aim was to determine whether multiple daily doses or an intermittent schedule will give the required “coverage” for anticancer activity. Methods: The accumulation of 14C-rucaparib and duration of PARP inhibition was determined in SW620 and BRCA2 mutant Capan-1 cells after a 30 minute pulse. Rucaparib concentration in plasma brain and Capan-1 tumor xenografts and PARP inhibition in brain and tumor was determined at intervals up to 1 week after a single dose of rucaparib. The efficacy of continuous and discontinuous schedules of rucaparib was determined in mice bearing Capan-1 xenografts. Results: Rucaparib accumulates in cells via a carrier-mediated transporter (Km of 8.4 ± 1.2 μM and Vmax of 469 ± 22 pmol/106cells/10 min) PARP activity in Capan-1 cells was suppressed by 80% for 72 hr after a pulse of 50 or 400 nM rucaparib, and still 40% reduced 7 days after 400 nM. Rucaparib was cleared rapidly from the plasma but it was detectable for up to 72 hr and suppressed PARP activity in the tumors for 7 days, being 25% and 10% of control after 10 mg/kg and 150 mg/kg, respectively. Peak levels in the brain were 2-10% of those in the tumor and only modest, transient PARP inhibition was observed in the brain. Tumor growth was suppressed by rucaparib at 150 mg/kg po on a weekly schedule as effectively as 10 mg/kg po on a daily x5 every week for 6 weeks. Conclusion: Rucaparib accumulates in human tumor cells and PARP inhibition by rucaparib is durable after a 30 min pulse. PARP is inhibited in tumor xenografts for up to 1 week after a single dose and when the drug concentrations are no longer detectable. Weekly dosing with rucaparib inhibits tumor growth. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C75. Citation Format: James C. Murray, Huw D. Thomas, Philip Berry, Suzanne Kyle, Christopher Jones, Ruth Plummer, Alan V. Boddy, Nicola J. Curtin. Rucaparib (CO-338) accumulation and persistence of PARP inhibition in vitro and in vivo and efficacy of intermittent vs continuous schedules. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C75.