Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
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DOI：
10.1016/s0140-6736(10)60892-6
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发表时间：
2010-07-24
期刊：
影响因子：
168.9
通讯作者：
Carmichael, James
中科院分区：
文献类型：
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作者：
Tutt, Andrew;Robson, Mark;Carmichael, James
背景：奥拉帕利布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缺陷细胞的合成致死。BRCA缺陷型卵巢癌的最大耐受剂量和最初的疗效信号已被报道。因此，我们评估了在患有BRCA1或BRCA2突变和晚期乳腺癌的女性中单独使用奥拉帕利的有效性、安全性和耐受性。方法在澳大利亚、德国、西班牙、瑞典、英国和美国的16个中心进行的第二阶段研究中，确诊为BRCA1或BRCA2突变和复发的晚期乳腺癌的女性(年龄为60岁)被分配到两个序贯队列中。第一组(n=27)连续口服奥拉帕利最大耐受量(每日两次，400 mg)，第二组(n=27)给予较低剂量(每日两次，每次100 mg)。主要疗效终点为客观有效率(ORR)。这项研究在ClinicalTrials.gov上注册，编号为NCT00494234。发现患者接受过之前三种化疗方案的中位数(队列1中的范围为1-5，队列2中的范围为2-4)。队列中27名患者(95%可信区间25-59)中有11名(41%)每天两次服用400 mg，队列中27名(11-41)中有6名(22%)每天服用100 mg。毒性反应以低毒为主。在每天两次服用400毫克的队列中，最常见的与原因相关的不良事件是疲劳(1级或2级，11[41%]；3级或4级，4级[15%])、恶心(1级或2级，11[41%]；3级或4级，4级[15%])、呕吐(1级或2级，3级[11%]；3级或4级，3级[11%])，以及贫血(1级或2级，1级[4%]；3级或4级，3级[11%])。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，11[41%]；没有3级或4级)和疲劳(1级或2级，7级[26%]；3级或4级，1[4%])。解释这项研究结果为BRCA缺陷型乳腺癌抑制PARP的概念提供了积极的证据，并为具有BRCA1相关或BRCA2相关DNA修复功能遗传丧失的肿瘤患者的新的靶向治疗策略显示了有利的治疗指标。具有BRCA1和BRCA2突变的女性的毒性与之前报道的那些没有这种突变的女性相似。
Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.Methods Women (aged years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234.Findings Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.