Pharmacokinetics and pharmacogenomics of ribociclib in black patients with metastatic breast cancer the LEANORA study

Abstract

Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan™ microarray (including CYP3A5*3, *6, and *7). CYP3A5 phenotypes varied among participants: 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve did not significantly differ between PMs (39,230 h*ng/mL) and IM/NMs (43,546 h*ng/mL; p = 0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes.

Fig. 1. Effect of CYP3A5 genotype on ribociclib metabolism in human liver microsomes.

Formation of major ribociclib metabolites over time was correlated with CYP3A5 genotype status. Human liver microsomes from a CYP3A5 NM (CYP3A5 *1/*1) had the greatest ribociclib metabolite formation followed by IM (CYP3A5 *1/*3) and PM (CYP3A5 *3/*3). Graphs represent three technical replicates per datapoint, error bars show standard deviation.

Fig. 2. P-values by different SNPs of interest and AUCtau by rs2246709.

2A Genetic data were available for all 14 exploratory candidate gene analysis participants. Variants are plotted by p-value with a dotted line representing a p-value of 0.05. This exploratory analysis of 14 participants identified one variant with a p < 0.05 for ribociclib AUC_TAU: CYP3A4 rs2246709 (p = 0.0041). 2B. This exploratory analysis identified an association between ribociclib area under the curve (AUC) in participants with a CYP3A4 variant (rs2246709), showing a higher AUC in those with A/G relative to those with A/A (p = 0.0041).

Fig. 3. Study design.

During screening, a swab CYP3A5 genotype was obtained to ensure adequate power. On C1D1, C1D8-16, and C2D1, blood counts and chemistries were obtained, as well as an electrocardiogram per standard of care. The list of concurrent medications was also obtained, and patients received a drug diary and patient-reported outcomes (CTCAE-PRO) questionnaires. Created with BioRender.com.