Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
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DOI：
10.1200/jco.2014.56.2728
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发表时间：
2015-01-20
期刊：
影响因子：
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通讯作者：
Domchek SM
中科院分区：
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作者：
Kaufman B;Shapira-Frommer R;Schmutzler RK;Audeh MW;Friedlander M;Balmaña J;Mitchell G;Fried G;Stemmer SM;Hubert A;Rosengarten O;Steiner M;Loman N;Bowen K;Fielding A;Domchek SM
奥拉帕尼是一种口服多聚（ADP-核糖）聚合酶抑制剂，对种系 BRCA1 和 BRCA2 (BRCA1/2) 相关乳腺癌和卵巢癌具有活性。我们评估了奥拉帕尼在一系列 BRCA1/2 相关癌症中的疗效和安全性。这项多中心 II 期研究招募了具有种系 BRCA1/2 突变和复发性癌症的个体。资格包括对先前铂类药物耐药的卵巢癌；患有转移性疾病且接受过至少三种化疗方案的乳腺癌；既往接受过吉西他滨治疗的胰腺癌；或经激素和一种全身治疗进展的前列腺癌。奥拉帕尼的给药剂量为 400 mg，每天两次。主要疗效终点是肿瘤反应率。共有 298 名患者接受了治疗并可进行评估。总体肿瘤缓解率为 26.2%（298 例中的 78 例；95% CI，21.3 至 31.6），31.1%（193 例中的 60 例；95% CI，24.6 至 38.1）、12.9%（62 例中的 8 例；95% CI，5.7 至 23.9）、21.7%（193 例中的 5 例；95% CI，5.7 至 23.9）。在卵巢癌、乳腺癌、胰腺癌和前列腺癌中分别为 23；95% CI，7.5 至 43.7）和 50.0%（八个中的四个；95% CI，15.7 至 84.3）。 42%的患者观察到疾病稳定≥8周（95% CI，36.0至47.4），包括40%（95% CI，33.4至47.7）、47%（95% CI，34.0至59.9）、35%（95% CI，16.4至57.3）和25%（95% CI， 3.2 至 65.1）分别患有卵巢癌、乳腺癌、胰腺癌或前列腺癌。最常见的不良事件 (AE) 是疲劳、恶心和呕吐。 54% 的患者报告了 ≥ 3 级 AE；贫血是最常见的（17%）。在与种系 BRCA1/2 突变相关的不同肿瘤类型中观察到对奥拉帕尼的反应。奥拉帕尼值得在验证性研究中进行进一步调查。
Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) –associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.