Abstract OT-26-03: Racial disparities in CYP3A variants in the metabolism of ribociclib in breast cancer patients

Abstract

Abstract Background:Ribociclib is an inhibitor of the cyclin dependent kinases 4 and 6 (CDK 4/6) and is approved in combination with endocrine therapy for patients with advanced hormone receptor (HR) positive metastatic breast cancer (mBC). CYP3A inhibitors increase ribociclib area under the curve (AUC) by 3.2-fold; this is of clinical concern given possible associations between exposure and toxicity (e.g., QTc prolongation and neutropenia). Although there is an FDA recommendation to modify therapy for patients prescribed CYP3A inhibitors, it is unknown if modifications are needed in patients who intrinsically lack enzyme activity (e.g., genetic CYP3A5 poor metabolizers). CYP3A function is largely derived from CYP3A4 and CYP3A5 isozymes in adults. It is difficult to differentiate relative contributions of CYP3A4 and CYP3A5 on CYP3A function due to sequence homology (~ 84%) and overlapping substrate specificity. Genetic variations in CYP3A5 can translate into poor, intermediate, or normal CYP3A5 metabolism of different substrates and some pharmaceutics metabolized by CYP3A have dosing recommendations based on genotype. We hypothesize that patients harboring genetic variants causing CYP3A5 poor metabolism experience increased exposure to ribociclib and likely more toxicities. Race is likely to be significant factor when exploring ribociclib pharmacokinetics (PK) and the role of CYP3A. There are known race-based differences in CYP3A4 and CYP3A5, with alleles associated with CYP3A5 loss prevalent in European Americans (EA) and not in African Americans (AA). Ribociclib PK have not been adequately studied in AA with 3% of participants in the pivotal trials AA. We aim to determine the pharmacokinetic and pharmacogenomic association between ribociclib exposure and CYP3A variants in AA and EA patients. Our findings should allow clinicians to tailor treatments to maintain therapeutic doses while limiting toxicities. Methods:This prospective, multicenter, open-label pilot study will assess ribociclib (600 mg PO daily) PK and pharmacogenomics in female patients with HR+/HER2- mBC. This design will be two independent, race-based cohorts: 18 AA patients and 18 EA patients. Eligibility include: female, >18, HR+/HER2- mBC and candidates for treatment with a CDK 4/6 inhibitor and endocrine therapy. Patients are ineligible if currently prescribed a medication that inhibits or induces the CYP3A isozymes, have baseline EKG abnormalities, or are otherwise considered to be ineligible for ribociclib. Participants will provide serial blood samples during the first cycle. Plasma samples will be analyzed via mass spectrometry to characterize the PK (e.g., AUC0-24, Cmax). Pharmacogenetic testing will be performed using the PharmacoScanTM microarray, which tests 4627 markers in 1191 genes, including 73 variants in CYP3A4 and CYP3A5. The primary endpoint will compare ribociclib AUC between CYP3A5 poor metabolizers vs. intermediate or normal CYP3A5 metabolizers within separate, race-based cohorts. Secondary endpoints include characterization of PK properties of ribociclib in the AA and EA populations. We also will seek to identify if CYP3A5, CYP3A4, or other variants are associated to different toxicity profiles. In addition, we will perform a hypothesis-generating PGx correlative analysis for potential biomarkers of ribociclib PK or toxicity. The primary outcome is powered to detect a minimum clinically meaningful change, a 2-fold change in AUC, which is less than the 3.2-fold change seen in the mentioned CYP3A drug interaction pharmacokinetic study. Based on CYP3A5 allelic frequencies, a sample size of 36 will provide 80% power to independently test the primary outcome in the two race-based cohorts. Funding: Breast Cancer Research Foundation. Contact: Sandra Swain MD, sandra.swain@georgetown.edu Citation Format: Ilana Schlam, D. Max Smith, Ian Chang, Asma Dilawari, Cody Peer, Tristan Sissung, Ming Tan, W. Douglas Figg, Sandra M. Swain. Racial disparities in CYP3A variants in the metabolism of ribociclib in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-26-03.