Abstract
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.
Highlights
Olaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor [1]
In the present retrospective multicenter study, we aimed to investigate the association between olaparib toxicity and potential explanatory factors, such as patient characteristics and olaparib plasma exposure, in patients treated for ovarian cancer in a real-life setting
Among 31 patients for whom at least one olaparib plasma concentration was available between November 2016 and August 2020, 4 were excluded
Summary
Olaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor [1]. By inhibitingPARP1 and PARP2, enzymes involved in DNA single-strand breaks (SSB) repair, olaparib leads to accumulation of SSB and subsequent deleterious double-strand breaks (DSB).While a cell with an intact homologous recombination (HR) pathway can repair theseDSB effectively, olaparib causes synthetic lethality in HR deficient tumor cells, such as in BRCA1/2-mutated cancers [2]. PARP1 and PARP2, enzymes involved in DNA single-strand breaks (SSB) repair, olaparib leads to accumulation of SSB and subsequent deleterious double-strand breaks (DSB). While a cell with an intact homologous recombination (HR) pathway can repair these. DSB effectively, olaparib causes synthetic lethality in HR deficient tumor cells, such as in BRCA1/2-mutated cancers [2]. Olaparib was initially developed for the treatment of HR-deficient cancers in patients carrying BRCA1/2 mutation [3]. Beyond BRCA1/2 mutations, a number of studies showed a survival benefit in patients affected by HRdeficient ovarian, breast, prostate or pancreatic cancers [4,5,6,7,8,9,10]. Clinical studies reported incidences of serious adverse events and dose reduction/
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