Exposure-Response Analyses of Olaparib in Real-Life Patients with Ovarian Cancer.

ABSTRACT

BACKGROUND: Olaparib is given in a fixed dose of twice-daily 300 mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient' cohort. METHODS: A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan-Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (Cmin), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the Cmin of patients who experienced toxicity was compared with patients who did not experience any toxicity. RESULTS: Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib Cmin of 1514 ng/mL. There was no statistical significant difference in PFS of patients below and above the median Cmin concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval 0.46-2.45, p = 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher Cmin of olaparib in comparison with patients who had not experienced any toxicity (n = 33), but it was not statistically significant (p = 0.069). CONCLUSIONS: Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.