Abstract
1581 Background: Ribo is metabolized by CYP3A and used for the treatment of patients with hormone receptor-positive (HR+)/HER2- mBC. FDA recommends dose reduction if used with CYP3A inhibitors due to a 3.2x increase ribo area-under-the-curve (AUC). It is unknown if modifications are needed in patients who lack enzyme activity (e.g., genetic CYP3A5 poor metabolizers (PM)). CYP3A5varies by genetic ancestry, is known to affect dosing for other drugs (e.g., tacrolimus). CYP3A5, ~85% of people of European ancestry are PM, ~85% of African ancestry are normal or intermediate metabolizers (NM, IM), which may impact ribo exposure and response. 2 percent (41/2066) enrolled in MONALEESA 2, 3, and 7 were Black. Methods: This prospective, multicenter cohort study (NCT04657679) assessed the PK and PGx of ribo (600 mg daily + letrozole/fulvestrant) in self-identified Black women with HR+/HER2- mBC. PK (0.5, 1, 2, 4, and 6 hours after ribo) and PGx studies were performed during cycle 1 via liquid chromatography with tandem mass spectrometry and PharmacoScan (ThermoFisher) microarray, which tests 1,191 genes. Including variants in CYP3A5*3, *6,and *7. Phenotypes assigned: PM (2 variant alleles), intermediate metabolism (IM; 1 variant allele), NM (0 variant alleles). The area under the curve (AUCtau) was compared with the exact Wilcoxon rank-sum test; Fisher’s exact test assessed the AEs and grade 3+ AEs to day 28. Results: 14 completed the trial. CYP3A5 phenotypes were PM (7), IM (6), and NM (1). The primary endpoint, AUCtau, was similar between CYP3A5 PM (39,230 hr*ng/mL; interquartile range [IQR]: 18,745 to 57,566 hr*ng/mL) vs. IM/NM (43,546 hr*ng/mL; IQR: 35,298 to 46,647 hr*ng/mL; p = 0.38). Other PK properties were similar between groups (table). There was a non-statistically significant higher number of AEs and grade 3+ AEs in PMs, when compared to NM/IMs. Study was not powered to assess differences in AEs. Conclusions: This cohort study detected no association between CYP3A5 genotype and ribo exposure. However, PMs may have more AEs relative to IMs/NMs. Future steps include exploring the impact of rare variants, including ~70 variants in CYP3A 4 and 5, on ribo exposure in this population. We will explore the role of clinical and genetic factors on the interindividual variability of ribo. Diverse patient representation in clinical trials is critical to ensure research findings are applicable to all patients. Clinical trial information: NCT04657679 .[Table: see text]
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