Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
复制标题
DOI：
10.1016/s0140-6736(10)60893-8
复制
发表时间：
2010-07-24
期刊：
影响因子：
168.9
通讯作者：
Tutt, Andrew
中科院分区：
文献类型：
--
作者：
Audeh, M. William;Carmichael, James;Tutt, Andrew
背景：奥拉帕利是一种新型的口服活性多聚(ADP-核糖)聚合酶(PARP)抑制剂，可诱导BRCA基因缺陷纯合子细胞的合成致死性。我们的目的是评估奥拉帕利治疗BRCA1或BRCA2突变患者的晚期卵巢癌的有效性和安全性。方法在这项国际化的多中心2期研究中，我们纳入了两个连续队列的女性(年龄和年龄=18岁)，这些患者都是BRCA1或BRCA2基因突变，且复发，可测量的疾病。这项研究在澳大利亚、德国、西班牙、瑞典和美国的12个中心进行。第1组(33例)口服奥拉帕布，最大耐受量为400 mg，每日2次；第2组(24例)，连续口服奥拉帕利100 mg，每日2次。主要疗效终点为客观有效率(ORR)。这项研究在ClinicalTrials.gov上注册，编号NCT00494442。发现患者之前接受过三种(范围1-16)化疗方案的中位数。在每天两次服用400 mg奥拉帕利布的33名患者(95%可信区间20-51)中，ORR为11例(33%)，在每天两次服用100 mg的24名队列患者中，ORR为3例(13%)。在每天服用两次奥拉帕利400毫克的患者中，最常见的与原因相关的不良事件是恶心(1级或2级[42%]；3级或4级，2级[6%])、疲劳(1级或2级，10[30%]；3级或4级，1级[3%])和贫血(1级或2级，5级[15%1；3级或4级，1级[3%])。在每天两次服用100毫克的队列中，最常见的与原因相关的不良事件是恶心(1级或2级，7例[29%]；3级或4级，2级[8%])和疲劳(1级或2级，9例[38%]；没有3级或4级)。这项第二阶段研究的解释结果为基因靶向治疗BRCA突变的晚期卵巢癌的有效性和耐受性提供了积极的证据。
Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations.Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >= 18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442.Findings Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2,14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%1; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4).Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.