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Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a Phase I multicentre trial in patients scheduled for elective breast cancer surgery

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Summary

Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4–5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.

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Acknowledgements

We thank the following investigators who also participated in the study: Jan Stencl (Bratislava Teaching Hospital, Bratislava, Slovakia), Olexandr Lytvynenko (Institute of Oncology AMS of Ukraine, Kiev, Ukraine), Fiona McCaig (Western General Hospital, Edinburgh, UK), Bohumil Nižnanský (National Cancer Institute, Bratislava, Slovakia), John Robertson (Academic Unit of Surgery, Nottingham, UK), Jan Lubinski (Pomeranian Medical University, Szczecin, Poland).

This study was sponsored by KuDOS Pharmaceuticals (formerly a subsidiary of AstraZeneca). Zoё van Helmond PhD from Mudskipper Bioscience, funded by AstraZeneca, assisted in the writing of this manuscript following discussion with and analysis of data by the authors. The final version has been approved by all authors.

Conflicts of interest

NB, JG, JJ, JE, VP, JC and JMD have no conflicts of interest to disclose. PMc, HS, MC are AstraZeneca employees and shareholders, and TP is also an employee of AstraZeneca.

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Author notes

  1. James Carmichael

    Present address: Celgene, Seville, Spain

Authors and Affiliations

  1. Department of Academic Surgery, Education and Research Centre, University Hospital of South Manchester, Wythenshawe, M23 9LT, Manchester, UK

    Nigel Bundred

  2. Hereditary Cancer Institute, Rīga Stradiņš University, Rīga, Latvia

    Janis Gardovskis

  3. Medical University of Gdansk, Gdansk, Poland

    Janusz Jaskiewicz

  4. Oncology Centre of Latvia, University of Latvia, Riga, Latvia

    Janis Eglitis

  5. Cherkassy Regional Oncology Centre, Cherkassy, Ukraine

    Viktor Paramonov

  6. AstraZeneca, Macclesfield, UK

    Peter McCormack, Helen Swaisland, Maria Cavallin, Tony Parry & James Carmichael

  7. Breakthrough Research Unit, Edinburgh Breast Unit, Western General Hospital, Edinburgh, UK

    J. Michael Dixon

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  1. Nigel Bundred
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Correspondence to Nigel Bundred.

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Bundred, N., Gardovskis, J., Jaskiewicz, J. et al. Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a Phase I multicentre trial in patients scheduled for elective breast cancer surgery. Invest New Drugs 31, 949–958 (2013). https://doi.org/10.1007/s10637-012-9922-7

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  • DOI: https://doi.org/10.1007/s10637-012-9922-7

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