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

https://doi.org/10.1016/j.critrevonc.2018.08.011Get rights and content

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 meta-analysis 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.

Section snippets

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

Aim

In order to assess by aggregate analysis the overall impact of PARPis in the management of EOC patients, we performed a systematic review of literature and we estimated this effect by a meta-analytic approach.

Study design

We performed a systematic review and meta-analysis of all published RCTs to evaluate the role of PARPis schedules compared to conventional therapies and wait-watchful approach in the management of EOC. In order to compare the different PARPis, we also performed an indirect-comparison meta-analysis in accordance with The Quality of Reporting of Meta-analyses (QUOROM) statements (Moher et al., 1999). The study includes therefore only prospective and RCTs on EOC in all treatment lines with PFS, as

Studies selection and characteristics

In Fig. 1, the PRISMA chart related to RCTs selection and search strategy is shown. In the time-frame covered by the present systematic review (2008–2018), 497 studies were reported as full papers or meeting abstracts, while 172 studies were initially excluded because reviews and/or for trial design. Subsequently, we examined in detail the remaining 325 trials. Among them, were excluded 76 and 46 trials respectively because selection criteria were not met and overlapping of other studies.

Discussion

This meta-analysis of 6 RCTs for a total of 1839 patients compares PARPi-based schedules to any other systemic conventional treatment and/or wait/watchful approach.

First of all, we confirmed the survival benefit for all PARPis individually and in the pooled analysis. In particular we evaluated a BRCAmt cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCAwt cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), in term of PFS in recurrent platinum-sensitive EOC.

Author contributions

DC, NS, PT, and PT designed the study.

DC, NS, EI e TDG did the literature search.

DC, NS, TDG extracted data. DC realized the figures.

EI and TDG performed the tables.

All authors collected data.

DC, NS, PT, and, PT interpreted and analyzed the data, and wrote the manuscript.

All authors read and approved final version of the manuscript.

Disclosures

Acknowledgments

This work has been supported by PhD program of Magna Graecia University: “molecular oncology and translational and innovative medical and surgical techniques”.

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    These authors contributed equally to this work.

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