Pharmacokinetic Boosting of Olaparib to Improve Exposure, Tolerance and Cost-effectiveness

NCT05078671 | Recruiting Phase 4

• 1 other identifier: PROACTIVE
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 10

Brief 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 enzyme 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.

Conditions

Cancer

Keywords

olaparib; pharmacokinetic enhancement

Outcome Measures

Primary Outcomes (3)

• Part A: Olaparib AUC0-12h

  The Area-Under-the-Curve (AUC) 0-12h of olaparib.

  2 weeks

• Part B: Progression-free survival (PFS)

  PFS is defined as time from randomization until the date of either objective radiological disease progression, or biochemical progression combined with clinical progression or death.

  12 months

• Part B: Dose reductions

  Number of patients who require a dose reduction due to toxicity.

  12 months

Secondary Outcomes (8)

• Part A: Inter- and intrapatient variability of AUC0-12h

  2 weeks

• Part A: Adverse events

  2 weeks

• Part B: Health status

  12 months

• Part B: Patient satisfaction

  12 months

• Part B: ctDNA

  12 weeks

Other Outcomes (2)

• Part A: Patient preference

  2 weeks

• Part B: Intratumoral olaparib

  At 8 weeks after start treatment and at the moment of progression

Study Arms (2)

Standard olaparib

ACTIVE COMPARATOR

Olaparib 300mg twice daily

Drug: Olaparib

Boosted olaparib

EXPERIMENTAL

Olaparib 100mg twice daily + cobicistat 150mg twice daily

Drug: Olaparib; Drug: Cobicistat

Interventions

Olaparib DRUG

olaparib treatment

Boosted olaparib; Standard olaparib

Cobicistat DRUG

Pharmacokinetic booster

Boosted olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects who are able and willing to provide written informed consent prior to screening;
• Age of 18 years or older;
• Able to measure the outcome of the study in this subject.
• Part A:
• Subjects who start or are on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Part B:
• Subjects who start on treatment with olaparib tablets 300mg twice daily, according to the drug label and physician's discretion;
• Expected to be on olaparib treatment for ≥ 3 months;
• ECOG performance status of 0-3.

You may not qualify if:

• Concurrent use of other anti-cancer therapies;
• Concurrent use of potent inducers or inhibitors of the cytochrome p450 enzyme 3A3 (CYP3A4) as assessed with the Dutch drug database "G-Standaard" of the Royal Dutch Pharmacists Association(KNMP);
• Known contra-indications for treatment with cobicistat in line with the summary of product characteristics;
• Subjects with renal insufficiency defined as estimated glomerular filtration rate \< 50 ml/min.

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (10)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

RECRUITING

Amsterdam Universitair Medische Centra

Amsterdam, Netherlands

RECRUITING

Netherlands Cancer Institute-Antoni van Leeuwenhoek

Amsterdam, Netherlands

RECRUITING

Amphia Ziekenhuis

Breda, Netherlands

RECRUITING

Universitair Medisch Centrum Groningen

Groningen, Netherlands

RECRUITING

Leiden University Medical Center

Leiden, Netherlands

RECRUITING

Maastricht UMC

Maastricht, Netherlands

RECRUITING

Radboudumc

Nijmegen, Netherlands

RECRUITING

ErasmusMC

Rotterdam, Netherlands

RECRUITING

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands

RECRUITING

Related Publications (3)

• Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, Ottevanger PB, Bloemendal HJ, Koolen SLW, Mathijssen RHJ, Boere IA, Hamberg P, Huitema ADR, Sonke GS, Opdam FL, Ter Heine R, van Erp NP. Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study). Eur J Cancer. 2023 Nov;194:113346. doi: 10.1016/j.ejca.2023.113346. Epub 2023 Sep 19.

  PMID: 37806255 RESULT

• Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, Sark M, Hovenier C, Kievit W, Ligtenberg MJL, Ottevanger PB, Bloemendal HJ, Koolen SLW, Mathijssen RHJ, Boere IA, Huitema ADR, Sonke GS, Opdam FL, Ter Heine R, van Erp NP. Pharmacokinetic boosting of olaparib: Study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B). Contemp Clin Trials Commun. 2025 Mar 29;45:101477. doi: 10.1016/j.conctc.2025.101477. eCollection 2025 Jun.

  PMID: 40248173 DERIVED

• Overbeek JK, van Erp NP, Burger DM, den Broeder AA, Koolen SLW, Huitema ADR, Ter Heine R. Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib. Clin Pharmacokinet. 2025 Mar;64(3):425-435. doi: 10.1007/s40262-025-01480-w. Epub 2025 Feb 5.

  PMID: 39909979 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

olaparib; Cobicistat

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nielka van Erp, prof. PharmD PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Joanneke K Overbeek, PharmD

CONTACT

+31-24-3617744; joanneke.overbeek@radboudumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Part A: cross-over normal olaparib versus boosted olaparib. Part B: normal olaparib versus boosted olaparib in two patient groups.

Study Record Dates

• First Submitted: September 22, 2021
• First Posted: October 14, 2021
• Study Start: December 15, 2021
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: June 12, 2024

Record last verified: 2024-06

Locations

NL (10)