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
Drug Development Unit, Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, Sutton, Surrey, United Kingdom.
N Engl J Med. 2009 Jul 9;361(2):123-34. doi: 10.1056/NEJMoa0900212. Epub 2009 Jun 24.
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.
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.
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.
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.)
抑制聚（腺苷二磷酸[ADP] - 核糖）聚合酶（PARP）是一种潜在的合成致死性治疗策略，用于治疗具有特定DNA修复缺陷的癌症，包括那些由BRCA1或BRCA2突变携带者发生的癌症。我们对一种新型、强效、口服活性PARP抑制剂奥拉帕尼（AZD2281）进行了人体临床评估。
这是一项1期试验，包括对奥拉帕尼的药代动力学和药效学特征进行分析。选择的目的是使研究人群中富含BRCA1或BRCA2突变携带者。
我们招募并治疗了60名患者；22名是BRCA1或BRCA2突变携带者，1名有BRCA相关癌症的强烈家族史但拒绝接受突变检测。奥拉帕尼的剂量和给药方案从每3周2次、每次10mg每日增加到每日2次、每次600mg连续给药。在每日2次接受400mg的8名患者中的1名（3级情绪改变和疲劳）以及每日2次接受600mg的5名患者中的2名（4级血小板减少症和3级嗜睡）中观察到可逆的剂量限制性毒性。这导致我们招募了另一个队列，仅由BRCA1或BRCA2突变携带者组成，以每日2次、每次200mg的剂量接受奥拉帕尼治疗。其他不良反应包括轻度胃肠道症状。在突变携带者中未观察到不良反应明显增加。药代动力学数据表明吸收和消除迅速；药效学研究证实了在外周血单核细胞和拔取的眉毛毛囊的替代样本以及肿瘤组织中PARP受到抑制。仅在突变携带者中报告了客观抗肿瘤活性，他们均患有卵巢癌、乳腺癌或前列腺癌并且接受过多种治疗方案。
奥拉帕尼几乎没有传统化疗的不良反应，可抑制PARP，并且在与BRCA1或BRCA2突变相关的癌症中具有抗肿瘤活性。（ClinicalTrials.gov编号，NCT00516373。）
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