Poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors as maintenance therapy in women with newly diagnosed ovarian cancer: a systematic review and meta-analysis

Abstract

Purpose To investigate the efficacy and safety of poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (including their different types) as maintenance therapy in women with newly diagnosed ovarian cancer, and to explore whether this therapy produces a survival benefit in a subgroup population with specific clinical characteristics. Methods We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science and relevant clinical research registry platforms on October 1, 2019, and included randomized controlled trials (RCTs) that compared PARP inhibitors with placebo in women (aged ≥ 18 years) with newly diagnosed epithelial ovarian cancer. Results We identified four RCTs with 3,070 participants. Compared with placebo, PARP inhibitor maintenance therapy showed a clinically significant benefit on progression free survival (PFS) in homologous recombination deficiency (HRD) positive population (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.29–0.53). In contrast, no clear differences were identified between the groups in the HRD negative population (HR, 0.83; 95% CI 0.67–1.03). Further, there was no clear difference between the groups in terms of other outcomes (overall survival, health-related quality of life, and adverse events). Conclusions PARP inhibitor maintenance therapy significantly prolongs the PFS of patients with newly diagnosed ovarian cancer, especially in HRD positive patients. The diagnostic test used to determine HRD status plays an important role in guiding PARP inhibitor maintenance therapy. Compared with placebo, the effect of PARP inhibitors on ovarian cancer was probably not affected by the International Federation of Gynecology and Obstetrics stage status, response to first-line chemotherapy, and residual macroscopic disease after debulking surgery.

Olaparib plus bevacizumab as a first-line maintenance treatment for patients with advanced ovarian cancer by molecular status: an updated PAOLA-1 based cost-effectiveness analysis

“…The model used in this study computed ICERs of olaparib plus bevacizumab versus bevacizumab alone were $249,579, $258,859, and $270,736 per QALY for patients with BRCA mutations, patients with HRD, and patients with HRD without BRCA mutations AOC, respectively. While not cost-effective, the combined olaparib plus bevacizumab regimen was associated with more favorable health benefits in patients with BRCA mutations and HRD-positive AOC, in line with several prior reports [ 37 38 39 40 ]. In two recent retrospective analyses of 33 and 42 patients in France and China harboring BRCA mutations or HRD-positive AOC, respectively, designed to assess prognostic outcomes associated with PARP inhibitor treatment, the median PFS and OS of patients with BRCA mutations were 20.9 vs. 37.7 months (p=0.210) and 151.2 vs. 122.5 months (p=0.520), while HRD status was an independent predictor of PFS (HR=0.67; 95% CI=0.49–0.92; p=0.010) [ 37 38 ].…”

“…In two recent retrospective analyses of 33 and 42 patients in France and China harboring BRCA mutations or HRD-positive AOC, respectively, designed to assess prognostic outcomes associated with PARP inhibitor treatment, the median PFS and OS of patients with BRCA mutations were 20.9 vs. 37.7 months (p=0.210) and 151.2 vs. 122.5 months (p=0.520), while HRD status was an independent predictor of PFS (HR=0.67; 95% CI=0.49–0.92; p=0.010) [ 37 38 ]. Two other meta-analyses including 5,005 and 3,070 patients with OC revealed significant PARP inhibitor-related improvements in the PFS of patients with BRCA mutations OC (HR=0.29; 95% CI=0.24–0.34 and 0.34; 0.28–0.41) and HRD-positive OC (HR=0.40; 95% CI=0.32–0.48 and 0.39; 0.29–0.53) [ 39 40 ]. As these new combination treatment regimens are associated with high costs, alternative treatments should be considered as appropriate for patients with AOC based on their molecular status, with the early detection of these prognostic biomarkers being vital to achieving optimal patient outcomes.…”

The cost-effectiveness analysis of maintenance olaparib plus Bevacizumab in patients with advanced ovarian cancer: based on the final survival results from PAOLA-1 trial

“…As such, the BRCA mutation status and HRD status of AOC patients were taken into consideration in the present study in an effort to provide better evidence-based guidance for both healthcare providers and payers. The calculated ICERs of olaparib plus bevacizumab versus bevacizumab monotherapy were $79,434/QALY, $141,636/QALY, and $ 200,595/QALY for BRCA mutations, HRD-positive, and HRD-positive without BRCA mutations AOC patients, respectively, suggesting that this combined treatment regimen is only cost-effective for the former two patient subgroups in line with prior evidence [ 40 – 43 ]. Two recent retrospective reports focused on 33 and 42 AOC patients in France and China with BRCA mutations or HRD-positive disease, respectively, found that PARP inhibitor treatment was associated with, the median PFS and OS in BRCA mutation-positive patients of 20.9 vs. 37.7 months (P = 0.21) and 151.2 vs. 122.5 months (P = 0.52), whereas HRD status was identified as an independent predictor of PFS (HR, 0.67; 95%CI, 0.49 to 0.92; P = 0.01)[ 40 , 41 ].…”

“…In two other meta-analyses enrolling 5,005 and 3,070 OC patients. PARP inhibitor treatment was associated with significantly improved PFS in both BRCA mutations (HR, 0.29; 95%CI, 0.24 to 0.34 and 0.34; 0.28 to 0.41) and HRD-positive (0.40; 0.32 to 0.48 and 0.39; 0.29 to 0.53) OC patients [ 42 , 43 ]. Given the high costs associated with these novel therapeutic regimens, alternative treatment options for AOC patients should be taken into consideration in light of their molecular status, and the evaluation of these prognostic biomarkers at an early time point remains essential to ensuring that these patients experience optimal.…”

Research progress on the role and mechanism of DNA damage repair in germ cell development

“…They found a significant clinical benefit of PARP inhibitors in progression-free survival (PFS) compared to placebo in maintenance therapy with homologous recombination deficiency (HRD). Therefore, maintenance therapy with PARP inhibitors can significantly prolong PFS in patients with newly diagnosed ovarian cancer ( 183 ).…”