The effect of PARP inhibitors in homologous recombination proficient ovarian cancer: meta-analysis

BRCA1/2 mutations and homologous recombination deficiency (HRD) predispose to increased sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor treatment. Our aim was to evaluate the PARP inhibitors effect on progression free survival (PFS) in a subpopulation with homologous recombination proficient status (HRD-BRCA-). A systematic literature search was performed for all studies reporting on the effect of PARP inhibitors regarding PFS in the HRD-BRCA- subpopulation, in patients with epithelial ovarian, tubal or primary peritoneal cancers (EOC). Five studies were included, enrolling a population of 3413 patients, with 1070 of them being HRD-BRCA-. PARP inhibitors were effective in the treatment of EOC, regardless of HRD and BRCA status or line of therapy. The estimated pooled effect hazard ratio (HR), assessing PFS for PARP inhibitors compared with control, was 0.76 (95% CI: 0.65–0.88, <i>I</i>² = 46%) in the HRD-BRCA- subpopulation. Comparing both subpopulations with HRD positive status (HRD+ BRCA+, HRD+ BRCA-) versus the HRD-BRCA-subpopulation, we have found statistically significant differences in the effect on PFS (P &lt; 0.05 for every interaction test) favouring HRD positive subpopulations (HRD+ BRCA+, HRD+ BRCA-). In the HRD-BRCA- subpopulation of patients, PARP inhibitors used as the second- or later-line of therapy showed more pronounced effect then when given as first line treatment (P = 0.04). Treatment of EOC with PARP inhibitors showed a significant effect regarding PFS in the HRD-BRCA- subpopulation, although a much higher benefit was evident for patients with HRD+ status (HRD+ BRCA+ and HRD+ BRCA-). In the HRD- subpopulation second line PARP inhibitor treatment showed greater benefit compared to first line PARP inhibitor treatment.

BRCA1/2突变与同源重组缺陷（homologous recombination deficiency, HRD）均会增强患者对聚腺苷二磷酸核糖聚合酶（poly(ADP-ribose)polymerase, PARP）抑制剂治疗的敏感性。本研究旨在评估PARP抑制剂对上皮性卵巢癌、输卵管癌或原发性腹膜癌（epithelial ovarian, tubal or primary peritoneal cancers, EOC）中同源重组正常且BRCA突变阴性（HRD-BRCA-）亚组患者无进展生存期（progression free survival, PFS）的影响。我们针对所有报道了PARP抑制剂对该HRD-BRCA-亚组患者无进展生存期影响的研究开展了系统性文献检索，最终纳入5项研究，共入组3413例患者，其中1070例属于HRD-BRCA-亚组。无论患者的HRD与BRCA状态如何，亦不论治疗线数，PARP抑制剂在上皮性卵巢癌的治疗中均展现出临床有效性。在HRD-BRCA-亚组中，PARP抑制剂相较对照组的无进展生存期合并风险比（hazard ratio, HR）估算值为0.76（95%置信区间（confidence interval, CI）：0.65~0.88，I²=46%）。将HRD阳性亚组（HRD+ BRCA+、HRD+ BRCA-）与HRD-BRCA-亚组进行对比，我们发现二者对无进展生存期的影响存在统计学显著性差异（所有交互检验P<0.05），且HRD阳性亚组的获益更为显著。在HRD-BRCA-亚组患者中，PARP抑制剂作为二线及以上治疗线时展现出的疗效优于一线治疗（P=0.04）。尽管HRD阳性患者（HRD+ BRCA+与HRD+ BRCA-）的获益更为显著，但PARP抑制剂治疗仍可使HRD-BRCA-亚组患者的无进展生存期得到显著改善。在HRD阴性亚组中，二线PARP抑制剂治疗相较一线治疗展现出更优的临床获益。