Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

Fong, Peter C.; Boss, David S.; Yap, Timothy A.; Tutt, Andrew; Wu, Peijun; Mergui-Roelvink, Marja; Mortimer, Peter; Swaisland, Helen; Lau, Alan; O'Connor, Mark J.; Ashworth, Alan; Carmichael, James; Kaye, Stan B.; Schellens, Jan H.M.; de Bono, Johann S.

doi:10.1056/nejmoa0900212

Cited by 3,634PARP inhibition in cancer therapyBRCA gene mutations in cancerAdvanced Breast Cancer Therapies

Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

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Fong, Peter C., Boss, David S., Yap, Timothy A., Tutt, Andrew, Wu, Peijun, Mergui-Roelvink, Marja, Mortimer, Peter, Swaisland, Helen +7 more·2009·New England Journal of Medicine

DOI 10.1056/nejmoa0900212

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Abstract

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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BRCA-mutated cancer cells are selectively sensitive to agents that require homologous recombination repair, such as PARP1 inhibitors.
“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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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: Fong, Peter C.
Yap, Timothy A.
Tutt, Andrew
Wu, Peijun
Mortimer, Peter
Lau, Alan
Ashworth, Alan
Kaye, Stan B.
Schellens, Jan H.M.
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
DOI: 10.1056/nejmoa0900212
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 › Pulmonary and Respiratory Medicine › 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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Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

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