Parkes Eileen E, Kennedy Richard D
Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, United Kingdom.
Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, United Kingdom Almac Diagnostics, Craigavon, United Kingdom
Oncologist. 2016 May;21(5):586-93. doi: 10.1634/theoncologist.2015-0438. Epub 2016 Mar 28.
: 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.
The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has recently received approval from the Food and Drug Administration (FDA) and European Medicines Agency (EMA), with a second agent (rucaparib) likely to be approved in the near future. However, the patient population with potential benefit from PARP inhibitors is likely wider than that of germline BRCA mutation-associated disease, and biomarkers are in development to enable the selection of patients with the potential for clinical benefit from these agents. Questions remain regarding the toxicities of PARP inhibitors, limiting the use of these agents in the prophylactic or adjuvant setting until more information is available. The indications for olaparib as indicated by the FDA and EMA are reviewed.
高级别浆液性卵巢癌的特征是基因组不稳定，所有肿瘤中有一半在同源重组这一重要的DNA修复途径中存在缺陷。鉴于聚（ADP-核糖）聚合酶（PARP）抑制剂可通过BRCA1/2缺失靶向作用于该修复途径存在缺陷的肿瘤，卵巢肿瘤可能是这种疗法临床应用的一个有吸引力的群体。在过去几年中，PARP抑制剂已进入临床实践，在过去2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批准奥拉帕利用于种系BRCA突变型卵巢癌的四线治疗，欧洲EMA批准奥拉帕利用于种系和体细胞BRCA突变型铂敏感卵巢癌的维持治疗。为了扩大能从PARP抑制剂中获益的卵巢癌患者群体，需要基于对作用机制的清晰理解来开发预测性生物标志物。此外，如果要在治愈性而非姑息性治疗中使用PARP抑制剂，还需要更好地了解其毒性特征。我们回顾了PARP抑制剂在I-III期临床试验中的进展，包括PARP抑制剂与化疗/抗血管生成药物的联合试验、这些药物的获批情况、耐药机制以及未解决的问题，包括生物标志物的开发以及这些药物长期血液学毒性的发生率。
聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕利最近已获得美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）的批准，第二种药物（鲁卡帕尼）可能在不久的将来获批。然而，可能从PARP抑制剂中获益的患者群体可能比种系BRCA突变相关疾病的患者群体更广泛，目前正在开发生物标志物，以便能够选择可能从这些药物中获得临床益处的患者。关于PARP抑制剂的毒性仍存在问题，在获得更多信息之前，限制了这些药物在预防性或辅助性治疗中的使用。本文回顾了FDA和EMA所指出的奥拉帕利的适应症。
