BC Cancer, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada.
BioDrugs. 2019 Jun;33(3):255-273. doi: 10.1007/s40259-019-00347-4.
As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, as it has high rates of homologous recombination (HR) deficiency. PARP inhibition exploits this cancer vulnerability by further disrupting DNA repair, thus leading to genomic catastrophe. Early clinical data demonstrated the effectiveness of PARP inhibition in women with recurrent EOC harbouring BRCA1/2 mutations and those with platinum-sensitive recurrences. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with recurrent EOC. Based upon randomised controlled trials, PARP inhibitors are in use as "maintenance" therapy for those with platinum-sensitive and platinum-responsive recurrences (irrespective of BRCA1/2 mutation status). Among women with BRCA1/2 mutations (either germline or somatic), maintenance PARP inhibitor therapy for those with recurrence has led to a nearly fourfold prolongation of progression-free survival compared to placebo control. Those without BRCA1/2 mutations experience an approximately twofold increase in progression-free survival. The latest clinical data demonstrate that women with BRCA1/2 mutations who respond to first-line chemotherapy and go on to have maintenance olaparib experience a doubling of the rate of freedom from death at 3 years when compared to placebo (60% vs 27%). PARP inhibitors are also approved as active therapy for women with germline or tumour BRCA1/2 mutations and recurrent EOC treated with three or more prior lines of therapy. Apart from the presence of a BRCA1/2 mutation (germline or somatic) and clinical factors such as platinum sensitivity and responsiveness, other predictive biomarkers are not in routine clinical use. Assays to identify genomic aberrations caused by HR deficiency, or mutations in genes involved in HR, have not been sufficiently sensitive to identify all patients who benefit from treatment. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, capable of re-establishing the DNA open-reading frame and leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair may also be important. This review focuses on the rationale for the use of PARP inhibitors in EOC. The data that have shaped clinical research are presented, and the trials that have changed management standards are reviewed and discussed. Highlighted are the past and ongoing efforts to further improve and explore the use of PARP inhibitors in EOC.
作为一类药物，聚（ADP-核糖）聚合酶（PARP）抑制剂对上皮性卵巢癌（EOC）的治疗产生了重大影响，特别是对最常见的组织学亚型——高级别浆液性癌，因为它具有很高的同源重组（HR）缺陷率。PARP 抑制通过进一步破坏 DNA 修复来利用这种癌症易感性，从而导致基因组灾难。早期临床数据表明，PARP 抑制剂在携带 BRCA1/2 突变的复发性 EOC 妇女和铂类敏感复发的妇女中具有疗效。三种 PARP 抑制剂（奥拉帕利、尼拉帕利和鲁卡帕利）现已获准用于复发性 EOC 妇女。基于随机对照试验，PARP 抑制剂被用作铂类敏感和铂类反应性复发（无论 BRCA1/2 突变状态如何）的“维持”治疗。在携带 BRCA1/2 突变（种系或体细胞）的妇女中，与安慰剂对照相比，维持 PARP 抑制剂治疗复发可使无进展生存期延长近四倍。没有 BRCA1/2 突变的妇女无进展生存期延长约两倍。最新的临床数据表明，在一线化疗中对 BRCA1/2 突变有反应并接受奥拉帕利维持治疗的 BRCA1/2 突变妇女，与安慰剂相比，3 年无死亡自由率增加一倍（60% vs 27%）。PARP 抑制剂也被批准用于携带种系或肿瘤 BRCA1/2 突变和接受三线或三线以上治疗的复发性 EOC 的妇女。除了存在 BRCA1/2 突变（种系或体细胞）和临床因素（如铂类敏感性和反应性）外，其他预测生物标志物尚未常规用于临床。用于识别 HR 缺陷引起的基因组异常或 HR 相关基因突变的检测方法还不够敏感，无法识别所有受益于治疗的患者。PARP 抑制剂耐药的机制包括 HR 基因中的回复突变恢复 HR，能够重新建立 DNA 开放阅读框并导致 HR 功能恢复。维持足够 DNA 修复的其他机制也可能很重要。本综述重点介绍了 PARP 抑制剂在 EOC 中的应用原理。介绍了形成临床研究的数据，并对改变管理标准的试验进行了回顾和讨论。强调了过去和正在努力进一步改进和探索 PARP 抑制剂在 EOC 中的应用。
