The Era of PARP inhibitors in ovarian cancer: “Class Action” or not? A systematic review and meta-analysis

Abstract

Introduction: Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis. Patients and Methods: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings. We considered the January 2008-April 2018 time frame. Progression free survival (PFS) was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios of grade 3-4 toxicity rates, were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by the fixed and random effect models. We conducted this metaanalysis to also compare indirectly the efficacy of different PARPis in EOC patients. Results: Five randomized trials for a total of 1839 patients were selected and included in the final analysis. In particular, we evaluated a BRCA-mutant cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCA-wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding safety profile, no significant differences were detected in all grade toxicities, however, taking into account 3-4 grade toxicities and SAEs (severe adverse events), we show that rucaparib-treated patients reported major abdominal pain events, while niraparib-treated patients were associated with the highest percentage of haematological toxicities, hypothesizing a drug effect for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents. Conclusions: We confirm a significant benefit in survival outcome of PARPis for EOC patients with a "class effect" on the bases of narrow CI and indirect comparisons in the different groups. Therefore, we underline that this strategy is of special value in BRCA-mutated patients because genetic testing allows best patient selection for all PARPis with the added value of individualized prevention in familiars. 1. Background Among epithelial ovarian cancer (EOC) patients, women with genetic predisposition show an early onset of disease. Rare high penetrant mutations in BRCA1 and BRCA2 genes greatly increase lifetime risk and account for the majority of hereditary cases, 10%-15% of all cases. These women have a 40-60% lifetime risk of EOC (44% in BRCA1 families and 27% in BRCA2 families, respectively) (Mavaddat et al., 2012; Xu et al., 2017). The gold standard first-line treatment is still based on the combination of carboplatin/paclitaxel (du Bois et al., 1997; Jayson et al., 2014). The management of recurrent disease strictly depends on

Efficacy and safety of PARP inhibitors as the maintenance therapy in ovarian cancer: a meta-analysis of nine randomized controlled trials

“…In ovarian cancer, these targeted inhibitors were the standard treatment for advanced serous ovarian cancer with BRCA mutation [35,36], and could also be used as alternative treatment for many patients other than BRCA germline mutation carriers [33,36]. At present, some scholars have analyzed the effect of PARPis on the treatment of ovarian cancer patients through meta-analysis [37,38]. However, more randomized controlled trials have been included in this study, including some of the latest clinical trials.…”

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

“…Many adverse events of PARPi treatment are class effects, meaning that all the drugs of the PARPi family are associated with these specific adverse events. 41 However, it is important to recognize specific drug-to-drug differences, including non-class effect adverse events as well as different incidence of the class effect adverse events. A meta-analysis examining the differences in toxicity between olaparib, niraparib, and rucaparib showed that hematologic adverse events were significantly related to niraparib, abdominal pain to rucaparib, and diarrhea to olaparib.…”

“…A meta-analysis examining the differences in toxicity between olaparib, niraparib, and rucaparib showed that hematologic adverse events were significantly related to niraparib, abdominal pain to rucaparib, and diarrhea to olaparib. 41 It is important to note that there is currently a recommendation to dose-adjust niraparib according to platelet level and weight at baseline, which was not yet incorporated in the trials assessed in the meta-analysis. 19 42 Table 3 summarizes adverse events in PARPi maintenance treatment in ovarian cancer in front-line and recurrent settings.…”

“…Grade ≥3 hematologic adverse events, especially thrombocytopenia, are more frequent with niraparib, in comparison with rucaparib, olaparib, and veliparib ( Table 3 ). 41 In fact, a retrospective analysis of NOVA and the dose escalation and expansion study data on niraparib identified that baseline body weight of <77 kg or platelet count of <1 50 000/µL were significant predictors for early dose modification. 42 The authors recommend a starting dose of 200 mg daily in those patients weighing <77 kg or with a platelet count <150×10 9 cells/L.…”

Front-Line Maintenance Therapy in Advanced Ovarian Cancer—Current Advances and Perspectives

“…Many AEs are class effects, such as cytopenia, but some are more dependent on the drug involved. A meta-analysis detected no significant differences in all grade hematologic AEs, more frequent in the initial months, however severe hematologic AEs were found to be more frequent with niraparib [ 47 ]. Niraparib is now recommended to be started at 200mg daily in patients with weight < 77 kg or with a low platelet count < 150 × 109 cells/L after a retrospective analysis of the NOVA trial [ 48 ].…”