METHODS: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high.
RESULTS: Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62).
CONCLUSIONS: Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.
方法:我们进行了数据库搜索,以比较PARPi与化疗的II期或III期随机临床试验,以及使用通用逆方差和随机效应模型的荟萃分析。根据其HRD状态对患者进行分类:(I)BRCAm(具有种系或体细胞起源的BRCA突变的患者);(II)非BRCAHRD[具有另一种HRD生物标志物gLOH或myChoice®的患者BRCA野生型(wt)];(III)同源重组能力(HRP)(BRCAwt且无HRD生物标志物)。从BRCAwt那里,我们将myChoice®+与gLOH-high进行了比较。
结果:纳入了5项研究(3,225例患者)在一线环境中分析了PARPi。BRCAmut患者的无进展生存期(PFS)的风险比(HR)为0.33[95%置信区间(CI):0.30-0.43];非BRCAHRD患者的PFSHR为0.49(95%CI:0.37-0.65),HRP患者的PFSHR为0.78(95%CI:0.58-1.03)。纳入了8项PARPi研究(5,529例患者),包括一线和复发设置。BRCAmut的PFSHR为0.37(95%CI:0.30-0.48),BRCAwt&HRD0.45(95%CI:0.37-0.55)和HRP0.70(95%CI:0.57-0.85)。BRCAwt和myChoice®≥42的患者的PFSHR为0.43(95%CI:0.34-0.56),与BRCAwt和gLOH高的患者相似,PFSHR为0.42(95%CI:0.28-0.62)。
结论:与HRP患者相比,HRD患者从PARPi获益更多。PARPi对HRP肿瘤患者的益处有限。仔细的成本效益分析,对于HRP肿瘤患者,应强烈考虑替代疗法或纳入临床试验.在BRCAwt患者中,gLOH-high和myChoice®+患者也有类似的获益.进一步的HRD生物标志物的临床开发(例如,Sig3)可能有助于识别更多受益于PARPi的患者。