Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness
Status:
Not yet recruiting
Trial end date:
2025-12-31
Target enrollment:
Participant gender:
Summary
Olaparib is a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor, originally used
for the maintenance treatment of women with platinum-sensitive relapsed breast cancer gene
(BRCA)-mutated high grade serious epithelial ovarian, fallopian tube, or peritoneal cancer,
who are in response to platinum-based chemotherapy. Over the last two years, several
therapeutic indications have been added to the drug label, such as first-line
platinum-sensitive BRCA-mutated high grade serious epithelial ovarian, fallopian tube, or
peritoneal cancer, germline BRCA1/2-mutated, human epidermal growth factor 2 (HER2-)negative,
locally advanced or metastatic breast cancer and BRCA1/2-mutated metastatic
castration-resistant prostate cancer, who have progressed following prior therapy. Since
olaparib is very expensive, this increase of treatment population will have a significant
impact on health care expenditures.
To keep healthcare affordable and accessible for all patients, innovative strategies are
warranted to reduce the dose of expensive drugs, without reduction of efficacy. For olaparib,
pharmacokinetic (PK) boosting can be applied. PK boosting is the lay term for administering a
non-therapeutic active strong inhibitor of a metabolic enzyme, for example the cytochrome
p450 enzym 3A (CYP3A), together with a therapeutic drug that is metabolized by the same
enzyme. Boosting thus increases the concentration of the therapeutic drug and allows lower
doses to be administered to patients. Hence, coadministration of a reduced dose of olaparib
with cobicistat, a non-therapeutic, strong inhibitor of the CYP3A can lead to equivalent
exposure to olaparib. Furthermore, inhibition of CYP3A could lead to less PK variability
since metabolic capacity is a prominent cause for (intra- and inter-individual) variability
in systemic exposure. Predictable olaparib exposure will reduce the number of patients who
are unintentionally under- or overtreated. Lastly, tumor tissue itself may express CYP3A as a
detoxification or resistance mechanism. Theoretically, PK boosting may also overcome
CYP3A-mediated drug resistance.
The purpose of this study is to establish the efficacy, safety and feasibility of
co-administering olaparib with the PK booster cobicistat with the aim to implement boosting
approach for olaparib in routine practice. The study is subdivided in two parts. In part A of
the study the equivalent exposure of boosted low dose olaparib is determined compared to the
normal dose. In part B of the study, non-inferiority of the boosted olaparib regimen will be
confirmed.