DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
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DOI：
10.1056/nejmoa1506859
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发表时间：
2015-10-29
期刊：
影响因子：
--
通讯作者：
de Bono JS
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作者：
Mateo J;Carreira S;Sandhu S;Miranda S;Mossop H;Perez-Lopez R;Nava Rodrigues D;Robinson D;Omlin A;Tunariu N;Boysen G;Porta N;Flohr P;Gillman A;Figueiredo I;Paulding C;Seed G;Jain S;Ralph C;Protheroe A;Hussain S;Jones R;Elliott T;McGovern U;Bianchini D;Goodall J;Zafeiriou Z;Williamson CT;Ferraldeschi R;Riisnaes R;Ebbs B;Fowler G;Roda D;Yuan W;Wu YM;Cao X;Brough R;Pemberton H;A'Hern R;Swain A;Kunju LP;Eeles R;Attard G;Lord CJ;Ashworth A;Rubin MA;Knudsen KE;Feng FY;Chinnaiyan AM;Hall E;de Bono JS
前列腺癌是一种异质性疾病，但目前的治疗并不是基于分子分层。我们假设有DNA修复缺陷的转移性、耐去势前列腺癌将对奥拉帕利抑制的聚腺二磷酸核糖聚合酶(PARP)有反应。我们进行了一项2期试验，对转移性、去势抵抗的前列腺癌患者进行奥拉帕利片治疗，剂量为400 mg，每天两次。主要终点是应答率，根据实体肿瘤反应评估标准1.1版，它被定义为客观反应，或前列腺特异性抗原水平至少下降50%，或循环肿瘤细胞计数从每7.5毫升血液中5个或更多细胞减少到每7.5毫升不到5个细胞。对强制肿瘤活检样本进行有针对性的下一代测序、外显子组和转录组分析以及数字聚合酶链式反应测试。总共有50名患者入选；所有患者都接受过多西他赛治疗，49名患者(98%)接受了阿比特龙或苯扎鲁胺治疗，29名患者(58%)接受了卡巴紫杉醇治疗。在可以评估的49名患者中，有16名患者有反应(33%；95%的可信区间为20-48)，其中12名患者接受了超过6个月的研究治疗。下一代测序在49名可以评估的患者中发现了16名DNA修复基因--包括BRCA1/2、ATM、Fanconi贫血基因和CHEK2--的纯合子缺失、有害突变或两者兼而有之。在这16例患者中，14例(88%)对奥拉帕利有反应，包括所有7例BRCA2缺失患者(4例双等位体细胞丢失，3例生殖系突变)和5例ATM异常中的4例。生物标志物试剂盒的特异度为94%。最常见的3级或4级不良反应是贫血(50名患者中的10名患者[20%])和疲劳(6名患者[12%])，这一发现与以前对奥拉帕利的研究一致。在前列腺癌对标准治疗无效和DNA修复基因缺陷的患者中，使用PARP抑制剂olaparib的治疗导致了高应答率。
Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition with olaparib. We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2 — in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate.