Pharmacokinetic boosting of olaparib to improve exposure, tolerance and cost-effectiveness (PROACTIVE-study)

Olaparib (Lynparza®) 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 Receptor 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
(~¤5700/month), 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 cytochrome P450 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 (Tybost®), 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.

This study has been transitioned to CTIS with ID 2024-516414-38-00 check the CTIS register for the current data.

Part A
Primary objective
1. To determine the equivalence of the Area-Under-the-Curve (AUC) of the
reduced, boosted dose of olaparib and the regular dose.

Secondary objectives
1. To determine whether boosting reduces the inter- and intrapatient PK
variability of olaparib;
2. To describe the safety of boosted olaparib.

Part B
Primary objectives
1. To determine if efficacy by progression-free survival (PFS) in patients with
high grade ovarian cancer receiving olaparib maintenance therapy who are in
response following completion of first-line platinum-based chemotherapy,
treated with the lower boosted dose of olaparib is non-inferior to patients
treated with the regular dose of olaparib;
2. To determine if tolerance by dose reductions due to toxicity in patients
treated with the lower boosted dose of olaparib is non-inferior to patients
treated with the regular dose of olaparib.

Secondary objectives
1. To investigate whether health status, tolerance and satisfaction of patients
treated with the boosted low dose olaparib is comparable to patients treated
with the regular dose of olaparib;
2. To evaluate whether treatment response of boosted versus regular olaparib
can be determined with cell-free tumor nucleic acids (ctDNA) as pharmacodynamic
biomarker;
3. To describe toxicity of the lower boosted dose of olaparib compared to the
regular dose of olaparib;
4. To compare cost-effectiveness of the lower boosted dose of olaparib compared
to the regular dose of olaparib.

Part A
A multicenter, randomized, open-label, crossover, drug-drug interaction study
in 18 patients.

Part B
A multicenter randomized, open-label, non-inferiority study in 142 patients.

The comparator treatment is the regular dose of olaparib tablets 300 mg BID,
250 mg BID or 200 mg BID based on the patient's condition and physician's
discretion.
The investigational treatment is the reduced dose of olaparib tablets 100 mg
BID, 150 mg OD or 100 mg OD, combined with the PK booster cobicistat 150 mg
BID.

A possible benefit of the intervention is less pharmacokinetic variability in
the group treated with the boosted olaparib dose.
The risk associated with this study are limited, since both treatment regimens
(comparator and intervention) are according to the drug label of olaparib.
Although the exposure to olaparib is increased in the interventional treatment
arm in part A compared to monotherapy, the boosted exposure was comparable to
an average exposure to olaparib in an unselected pupation. Therefore, the
additional risks due to side effects in the interventional treatment arm in
part B is considered negligible. Many patients treated with olaparib experience
side effects. These side effects are considered mild and easily manageable with
dose reductions. The most common side effects are bone marrow depressions which
- when adequately managed - do not interfere with the quality of life of
patients. Since all patients will be adequately monitored in line with standard
care, the additional risk for side effects in the interventional treatment arm
is expected to be comparable to the comparator arm.
The burden for subjects participating in this study is mainly time-investment
associated with the study visits, additional questionnaires, the additional
number of blood samples in part A of the study and tumor biopsies if consented
in part B of the study. The majority of participating will have to take an
additional drug, cobicistat, which increases burden of medication intake. In
these subjects, we will carefully evaluate potential drug interactions to
guarantee safety.