Medical Oncology Department, B-ARGO Group, Institut Català d'Oncologia Badalona, Carretera del Canyet s/n, 08916 Badalona, Spain.
Campus de la UAB, Universitat Autónoma de Barcelona, Plaça Cívica, 08193 Bellaterra, Spain.
Int J Mol Sci. 2018 Oct 19;19(10):3249. doi: 10.3390/ijms19103249.
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with 1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of 1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations.
同源重组（HR）是一种 DNA 修复途径，在 50%的高级别浆液性卵巢癌（HGSOC）中存在缺陷。由于聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi；奥拉帕利、尼拉帕利和鲁卡帕利已商业化），HR 缺陷（DHR）为这些患者提供了治疗机会。尽管最初，PARPi 是为 1/2 突变的患者开发的，但强有力的临床数据表明，它们在没有 DHR 的更广泛人群中也有获益。这一突破在日常实践中引发了几个需要进一步研究的问题：如何选择最受益于 PARPi 的人群？PARPi 应该在卵巢癌的哪个阶段使用？有哪些合理的策略可以克服 PARPi 耐药性？在本文中，我们从转化的角度总结了文献，并讨论了目前涉及 PARPi 的临床研究（在审查 ClinicalTrials.gov 后）。目前正在进行研究 DHR 的功能生物标志物和临床试验，以测试 PARPi 作为一线治疗或再次治疗的获益。此外，在临床环境中，仅鉴定出 1/2 的二次恢复突变作为诱导 PARPi 耐药的事件。这种以及其他在临床前描述的机制在临床中的频率尚不清楚。研究 PARPi 耐药的机制对于指导药物联合的临床开发非常重要。
