LAUSR

Background: Palbociclib (PAL) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that is under investigation in multiple oncologic clinical trials and is currently approved for use in combination with aromatase inhibitors (AIs) or fulvestrant (FUL) in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (BC). The PEARL Study is an ongoing international, open label, controlled, randomized Phase 3 study comparing the efficacy and safety of PAL in combination with endocrine therapy (exemestane [EXE] or FUL) versus capecitabine in postmenopausal women with HR+/ HER2– metastatic BC whose disease progressed on AIs. A secondary objective of the study was to evaluate the pharmacokinetics (PK) of PAL (125mg QD, 3 weeks on/1 week off) and EXE (25mg QD, continuously) when coadministered. This is the first study to investigate the drug-drug interaction (DDI) potential of the combination of PAL and the AI EXE. Methods: Patients (pts) randomized to the PAL+EXE arm of the PEARL Study in seven selected sites had the option of participating in the PK sub-study. Those who enrolled in the PK sub-study received EXE alone in a 7-day lead-in period immediately prior to Cycle 1 Day 1, when both drugs were coadministered on their standard dosing regimens. Sub-study pts were to have 2 pre-dose plasma PK samples drawn at steady-state (ss) during the lead-in period ("EXE Alone") for EXE determination, and 2 ss PK samples drawn for EXE and PAL determination (2 per analyte) during coadministration ("PAL+EXE"). Plasma concentrations of PAL and EXE were measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The withinpatient mean concentration of the PK samples which met ss acceptance criteria (WPM-C trough ) for each analyte were generated for each treatment period as the input for DDI analyses. To assess the effect of coadministration of PAL on EXE PK, the WPM-C trough of EXE was compared within patients between the "PAL+EXE" (Test) and "EXE Alone" (Reference) treatment periods using a one-way analysis of variance (ANOVA) model with treatment as a fixed effect and patient as a random effect. To assess the effect of coadministration of EXE on PAL PK, the WPM-C trough of PAL was compared between the "PAL+EXE" period (Test) and historical data (Reference) using an ANOVA model. Analysis of covariance (ANCOVA) models were used to assess the impact of demographic differences between analysis populations in covariates known to impact PAL PK on the ANOVA model conclusions. Results: A total of 26 pts randomized to the PAL+EXE arm were enrolled in the PK sub-study and had PK samples analysed, of which 23 meet ss acceptance criteria. The ratio of the adjusted geometric means for EXE WPM-C trough was 106.9% (90%CI: 82.4-138.8), when EXE was administered with PAL, compared with its administration alone. Likewise, the models to assess potential for EXE to perpetrate DDI on PAL PK showed ratios of adjusted geometric means of 102.4% (90%CI: 82.0-127.9) and 111.6% (90%CI: 90.3137.8), when adjusted for covariates. Conclusion: The PK data indicate a lack of a clinically meaningful DDI between PAL and EXE when the 2 drugs are coadministered. Sponsor: GEICAM Citation Format: Martin M, Hoffman J, Ruiz-Borrego M, Munoz M, Calvo L, Crownover P, Garcia-Saenz JA, Alba E, Wang D, Thallinger C, Stradella A, Montano A, Adamo B, Antolin S, Moreno-Anton F, Falo C, Ruiz V, Martin N, Caballero R, Carrasco E, Gil-Gil M. Evaluation of the drug interaction potential of palbociclib and exemestane – Results from the PEARL pharmacokinetic sub-Study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-23.