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

Crit Rev Oncol Hematol. 2018 Nov;131:83-89. doi: 10.1016/j.critrevonc.2018.08.011. Epub 2018 Sep 3.

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.

Keywords: Maintenance therapy; Meta-analysis; Ovarian cancer; PARP inhibitors; Randomized clinical trials.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Female
  • Humans
  • Ovarian Neoplasms / drug therapy*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Prognosis

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly (ADP-Ribose) Polymerase-1