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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Open accessAbstract
BACKGROUND: The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. METHODS: This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. RESULTS: We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. CONCLUSIONS: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373.)
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“Thus, BRCA-mutated cancer cells are selectively sensitive to agents that require repair of double-strand breaks by homologous recombination, such as PARP1 inhibitors [5–7].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [7]
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“This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.”
Metadata
- Authors
- Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., Ashworth, A., Carmichael, J., Kaye, S. B., Schellens, J. H. M., & de Bono, J. S.
- Affiliations
- National Health Service (GB)
- The Netherlands Cancer Institute (NL)
- Institute of Cancer Research (GB)
- AstraZeneca (United Kingdom) (GB)
- Utrecht University (NL)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-07-09
- Volume
- 361
- Issue
- 2
- Pages
- 123-134
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2171972386
- Cited by
- 3,634
- References
- 30
- Citations by year
- 2026: 79 · 2025: 113 · 2024: 126 · 2023: 152 · 2022: 188 · 2021: 189 · 2020: 173 · 2019: 195 · 2018: 190 · 2017: 214 · 2016: 249 · 2015: 252 · 2014: 244 · 2013: 247 · 2012: 285
- FWCI
- 170.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- AstraZeneca
- Royal Marsden NHS Foundation Trust
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Cancer Research UK (A8363)
- National Institute for Health and Care Research
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Keywords
- olaparib, PARP inhibitors, BRCA1 mutation carriers, BRCA2 mutation carriers, synthetic lethality, DNA repair deficiency, ovarian cancer, breast cancer, prostate cancer, pharmacokinetics, pharmacodynamics, dose-limiting toxicity, thrombocytopenia, anticancer activity
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Female, Heterozygote, Humans, Male, Middle Aged, Neoplasms, Phthalazines, Piperazines, Drug Design, Germ-Line Mutation, Genes, BRCA1, Genes, BRCA2, Young Adult
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