Abstract 3888: Intracranial evaluation of the in vivo pharmacokinetics, brain distribution, and efficacy of rucaparib in BRCA-mutant, triple-negative breast cancer

Abstract

Abstract Background: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for use in recurrent ovarian cancer; however, there are limited data on the activity of rucaparib in patients with central nervous system (CNS) involvement. The goals of these studies were to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of rucaparib and to correlate these results with the efficacy observed in a BRCA1-mutant xenograft model of triple-negative breast cancer (TNBC). In addition, a case report where rucaparib demonstrated clinical activity in the CNS of a patient with BRCA2-mutant breast cancer is presented. Methods and Results: In a PK study in CD-1 mice, rucaparib demonstrated limited brain penetration after a single oral dose of 150 mg/kg, with a mean free brain-to-plasma AUC ratio (Kpuu, brain) of 0.09. The free brain Cmax of rucaparib was 8.59 ng/mL, which was comparable to its free cerebrospinal fluid Cmax (6.69 ng/mL) but significantly lower than the total Cmax measured in the brain (118 ng/mL). The antitumor efficacy of rucaparib was evaluated in orthotopic and intracranial tumor models using the BRCA1-mutant MDA-MB-436 TNBC cell line. In the orthotopic setting, rucaparib ≥50 mg/kg BID resulted in >100% tumor growth inhibition (TGI) after 28 days of dosing. Higher levels of rucaparib were observed in the tumor relative to plasma at all doses evaluated. A PK-PD analysis showed an inverse correlation between poly(ADP-ribose) and rucaparib levels in the plasma and tumor, with decreased poly(ADP-ribose) levels correlating with greater TGI. To evaluate intracranial efficacy, a luciferase labelled MDA-MB-436 cell line was employed and tumor burden was evaluated by weekly bioluminescence measurements. Rucaparib 150 mg/kg BID demonstrated efficient suppression of tumor growth after 43 days of dosing, with >100% TGI. In support of these preclinical findings, a patient with germline BRCA2-mutant metastatic breast cancer who had progressive CNS disease following whole brain radiation therapy was treated with rucaparib 600 mg PO BID for 9 months under a compassionate use program. A reduction of multiple metastatic brain lesions was observed based on MRI scans taken before and after rucaparib treatment. The patient also experienced complete resolution of neurological symptoms. Conclusions: In vivo PK studies confirmed the limited brain penetration of rucaparib in a murine model with an intact blood-brain barrier. Nevertheless, antitumor efficacy was observed in a BRCA1-mutant intracranial TNBC mouse model, and clinical activity has been observed in a patient with germline BRCA2-mutant breast cancer and CNS involvement who was treated with rucaparib. Further studies are warranted to elucidate the activity of rucaparib in the brain. Citation Format: Minh Nguyen, Liliane Robillard, Thomas C. Harding, Jim J. Xiao, Andrew D. Simmons, Hartmut Kristeleit, Michelle (Mingxiang) Liao. Intracranial evaluation of the in vivo pharmacokinetics, brain distribution, and efficacy of rucaparib in BRCA-mutant, triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3888.