Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer
Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer
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DOI：
10.1634/theoncologist.2015-0438
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发表时间：
2016-05-01
期刊：
影响因子：
5.8
通讯作者：
Kennedy, Richard D.
中科院分区：
文献类型：
--
作者：
Parkes, Eileen E.;Kennedy, Richard D.
高级别浆液性卵巢癌的特点是基因组不稳定，一半的肿瘤在同源重组的重要 DNA 修复途径中表现出缺陷。鉴于聚（ADP-核糖）聚合酶（PARP）抑制剂在靶向因 BRCA1/2 缺失而导致修复途径缺陷的肿瘤中的作用，卵巢肿瘤可能是该疗法临床应用的一个有吸引力的群体。 PARP抑制剂在过去几年中已进入临床实践，并在过去两年内获得了美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）的批准。美国 FDA 批准奥拉帕尼适用于种系 BRCA 突变卵巢癌的四线治疗，欧洲 EMA 批准奥拉帕尼用于种系和体细胞 BRCA 突变铂敏感卵巢癌的维持治疗。为了扩大受益于 PARP 抑制剂的卵巢癌患者群体，需要基于对作用机制的清晰了解的预测生物标志物。此外，如果 PARP 抑制剂用于治疗而非姑息治疗，则需要更好地了解其毒性特征。我们回顾了PARP抑制剂I-III期临床试验的进展，包括PARP抑制剂与化疗/抗血管生成药物的联合试验、这些药物的批准情况、耐药机制以及尚未解决的问题，包括生物标志物的开发和这些药物的长期血液毒性发生率。
High-grade serous ovarian cancer is characterized by genomic instability, with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Given the action of poly(ADP-ribose) polymerase (PARP) inhibitors in targeting tumors with deficiencies in this repair pathway by loss of BRCA1/2, ovarian tumors could be an attractive population for clinical application of this therapy. PARP inhibitors have moved into clinical practice in the past few years, with approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA) within the past 2 years. The U.S. FDA approval of olaparib applies to fourth line treatment in germline BRCA-mutant ovarian cancer, and European EMA approval to olaparib maintenance in both germline and somatic BRCA-mutant platinum-sensitive ovarian cancer. In order to widen the ovarian cancer patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clear understanding of the mechanism of action are required. Additionally, a better understanding of the toxicity profile is needed if PARP inhibitors are to be used in the curative, rather than the palliative, setting. We reviewed the development of PARP inhibitors in phase I-III clinical trials, including combination trials of PARP inhibitors and chemotherapy/antiangiogenics, the approval for these agents, the mechanisms of resistance, and the outstanding issues, including the development of biomarkers and the rate of long-term hematologic toxicities with these agents.