Gao Lili, Chen Rui, Li Ting, Li Lujin, Zheng Qingshan
Center for Drug Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Pharmacol. 2021 Nov 8;12:771836. doi: 10.3389/fphar.2021.771836. eCollection 2021.
This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC). The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated. The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively. PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.
本研究旨在建立药效学模型并筛选合理的协变量，以定量描述聚（ADP - 核糖）聚合酶抑制剂（PARPis）作为复发性卵巢癌（ROC）维持治疗的疗效。利用来自FDA批准的PARP抑制剂（奥拉帕利、尼拉帕利和鲁卡帕利）已发表随机试验的1169例患者的无进展生存期（PFS）数据，建立对数正态风险函数模型。采用蒙特卡罗模拟比较不同情况下的PFS值，如单药治疗（单独给药）和联合治疗（PARPis与化疗或靶向治疗联合）、不同生物标志物状态以及不同PARP抑制剂。还对PFS进行了估计。研究表明，单药治疗的中位PFS为8.5个月，联合治疗为16.0个月。单药治疗时，BRCA突变、BRCA野生型和HRD阳性患者的中位PFS分别为11.0、7.5和9.0个月，联合治疗时分别为23.0、14.0和17.5个月。此外，奥拉帕利、尼拉帕利和鲁卡帕利单药治疗的中位PFS分别约为9.5、10.5和12.0个月，联合治疗时分别约为19.0、20.0和25个月。与西地尼布、贝伐单抗和化疗联合时的中位PFS值分别约为17.0、12.5和19.5个月。PARPi联合治疗作为ROC的维持治疗比单药治疗更有效，且PARPis与化疗联合的疗效高于与抗血管生成药物联合。我们发现BRCA野生型的PFS与HRD阳性患者相似，奥拉帕利、尼拉帕利和鲁卡帕利之间的PFS无显著差异，这为PARPis治疗ROC的临床实践提供了必要的定量信息。
