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Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours

Abstract

Introduction

The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.

Methods

During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1–5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10–13, 20 mg qd days 14–26; cohort 2, anastrozole 1 mg qd days 10–19; cohort 3, letrozole 2.5 mg qd days 10–38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.

Results

Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0–τ decreased by 20% (90% CI 0.71–0.90) and 27% (0.63–0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0–τ increased by 13% (1.06–1.22) and 16% (1.11–1.21), respectively]; however, the 90% CI fell within the 0.7–1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.

Conclusions

The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.

Funding

AstraZeneca.

Clinical Trial Registration

NCT02093351.

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Acknowledgements

The authors would like to thank the patients who took part in the study and Dr. Marlies Langenberg, UMC Utrecht, for her contribution as a trial investigator.

Funding

This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co., Inc. Article processing charges and the Open Access fee were also funded by AstraZeneca and Merck & Co., Inc. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Medical Writing and other Editorial Assistance

Medical writing assistance was provided by Lizzie Wilkins PhD, of Mudskipper Business Ltd, funded by AstraZeneca and Merck and Co, Inc. The UK centres involved were Experimental Cancer Medicine Centres supported by Cancer Research UK and the Department of Health.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval of the version to be published.

Disclosures

Christian Rolfo has received research grants from OncoDNA, honoraria from Mylan and speakers’ fees from MSD, Novartis and Guardant Health. Their current affiliation is University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA. Jacques De Grève has received travel grants from AstraZeneca. Guy Jerusalem has received investigator fees to his institution from AstraZeneca and grants and personal fees from Novartis, Roche, Pfizer, Lilly, Celgene, Amgen, BMS, Puma and Daiichi Sankyo. Carsten Goessl is an employee of AstraZeneca and owns stock. Maria Learoyd is an employee of AstraZeneca and owns stock. Christopher Bailey is an employee of AstraZeneca and owns stock. Joseph Birkett has received consulting fees from AstraZeneca, their current affiliation is Crest Pharma Ltd, Surrey, UK. Stuart Spencer is an employee of Plus-Project contracted to AstraZeneca and owns shares in AstraZeneca. At the time of the study Emma Dean worked at The Christie NHS Foundation Trust, the University of Manchester, Manchester, UK. Since completion of this study, Emma Dean has taken up employment with AstraZeneca and owns stock. At the time of the study, Rhoda Molife worked for The Royal Marsden and Institute of Cancer Research, Sutton, UK. Their current affiliation is MSD, London, UK. Ruth Plummer, Henk Verheul, Filip De Vos, Karin Leunen, Peter Grundtvig-Sørensen, Sylvie Rottey, Antoine Italiano, James Spicer and Luc Dirix have nothing to disclose.

Compliance with Ethics Guidelines

The institutional review boards or independent ethics committees of all investigational sites approved the protocol. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, the 1964 Helsinki declaration and its later amendments or comparable ethical standards, Good Clinical Practice, and the AstraZeneca policy on bioethics. Informed consent was obtained from all individual participants included in the study.

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Correspondence to Ruth Plummer.

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Plummer, R., Verheul, H.M., De Vos, F.Y.F.L. et al. Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Adv Ther 35, 1945–1964 (2018). https://doi.org/10.1007/s12325-018-0804-z

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Keywords

  • Anastrozole
  • Antihormonal therapy
  • Endocrine therapy
  • Letrozole
  • Lynparza
  • Olaparib
  • PARP inhibitor
  • Pharmacokinetics
  • Safety
  • Tamoxifen