Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

• Main Authors: Maud Velev, Alicja Puszkiel, Benoit Blanchet, Sixtine de Percin, Nicolas Delanoy, Jacques Medioni, Claire Gervais, David Balakirouchenane, Nihel Khoudour, Patricia Pautier, Alexandra Leary, Zahra Ajgal, Laure Hirsch, François Goldwasser, Jerome Alexandre, Guillaume Beinse
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Pharmaceuticals
• Subjects: olaparib; population pharmacokinetics; PK-toxicity relationship; ovarian cancer; therapeutic drug monitoring
• Online Access: https://www.mdpi.com/1424-8247/14/8/804

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.