Systematic or Meta-analysis StudiesParp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status☆
Introduction
It is by now widely recognized that ovarian cancer (OC) harbours a remarkable degree of genomic disarray and instability and presents with a wide range of mutations [1], [2]. Indeed, around 50% of all high-grade serous ovarian tumours are estimated to have a deficiency in the homologous recombination (HR) DNA repair mechanism, with about 15% of carcinomas harbouring a germline and 6% a somatic Breast Related Cancer Antigens (BRCA) 1–2 mutation. These mutations confer to the cell a disability to repair DNA through the HR pathway, leading to a condition defined as homologous recombination deficiency (HRD) [1], [3]. HRD as a condition, is not exclusively defined by deleterious BRCA 1 and 2 mutations, but by genomic alterations and/or epigenetic silencing of other pathway genes as well, including ATR, ATM, RAD51/54, CHK1/2, NBS1, PTEN and PALB2 [1], [3], [4]. These genetic and epigenetic aberrations grant the so-called “BRCA-ness” profile, resulting in a disability of affected cells to correctly repair DNA double strand breaks, much like a BRCA mutation. Consequently, a “BRCA-ness” profile encompasses a susceptibility to DNA-damaging agents, just like a BRCA mutation. A deficiency in the HR pathway alone implies no threat to the cell, as other DNA repair mechanism are able to compensate for it. If, however, the cell suffers a deficiency of other DNA repair mechanisms, or if other DNA repair mechanisms were somehow inhibited, the resulting accumulated DNA damage would ultimately lead to cell death [5]. This defines the concept of synthetic lethality, a process by which cancer cells are selectively targeted by the inactivation of two genes or pathways, when inactivation of either gene or pathway alone, is nonlethal [5].
This increasing knowledge regarding the molecular and genetic aspects underlying OC has enabled the possibility to exploit new therapeutic strategies that aim to maximize benefits and limit adverse effects, guided by a patient-tailored principle. One of the most studied groups of novel chemotherapeutic agents is that of the Poly-ADP-Ribose Polymerase (PARP) inhibitors (PARPis), which, along with Vascular Endothelial Growth Factor (VEGF) inhibitors have improved to some extent the maintenance-therapy landscape in OC [2].
Poly-ADP-Ribose Polymerase (PARP) is a family of 17 enzymes with proven DNA repair activity, through the Base Excision Repair (BER) mechanism, with PARP1 being responsible for 85% of it. Their physiological activity requires the consumption of NAD+ and the release of nicotinamide, which is exactly the primary target for PARP inhibition, thus PARP inhibitors (PARPis) are defined as b-nicotinamide adenine dinucleotide (NAD+)-competitive inhibitors [6], [7]. It has been recently suggested that “PARP trapping”, described as a situation where PARP-1, inactivated by the PARPis, remains trapped to the site of DNA damage, forming toxic PARP–DNA complexes, thus preventing further DNA repair [6], [8], might be another mechanism through which PARPis mediate their activity. Other proposed mechanisms of action of PARPis include promotion of increased non-homologous end joining and impairment of BRCA1 recruitment to the site of DNA damage [9], [10]. However, in a cell incapable of adequately employing HR, PARP inhibition would cause accumulation of unrepaired DNA damage, and subsequent cell death, falling into the category of the aforementioned synthetic lethality. This is why the development of PARPis as potential treatment agents in OC, initially focused only on BRCA-mutated tumours [11]. However, despite the fact that the majority of studies regarding PARPis in OC report higher effectiveness in BRCA mutated women, this class of drugs appears to have some efficacy in BRCA wild type patients as well. Moreover, the prognostic significance of the BRCA-ness phenotype is not fully clear and it is still uncertain whether these patients effectively have better response rates to conventional or novel chemotherapeutic agents. In this scenario, the aim of this meta-analysis is to investigate the effectiveness of PARPis as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC) by paying particular attention to the population’s BRCA status of mutation and stratifying results into five different categories: whole population, germ-line BRCA mutated patients, somatic BRCA mutated patients, patients with HRD and wild type population.
Section snippets
Eligibility criteria
The inclusion criteria for the meta-analysis were: (1) randomized study with patients affected by platinum-sensitive ROC, where PARPis were used in a maintenance setting after a platinum based chemotherapy; (2) study that randomly compared a PARPi to placebo in terms of progression free survival (PFS). Only articles written in English were included. Studies including combinations of PARPis with chemotherapy were excluded [12].
Search strategies
Two independent reviewers searched through PubMed, Medline, Scopus,
Results
This meta-analysis reports results in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [14].
The electronic search resulted in the pre-selection of 20 full-text articles overall (Fig. 1). Following thorough evaluation of each record, 15 studies were excluded. Four articles were not pertinent to our theme; three studies investigated costs related to PARPis treatment; three records were excluded as PARPis were not investigated against
Discussion
Around 50% of all HGSOC are estimated to have HRD with about 15% of carcinomas harbouring a germline BRCA mutation, 6% a somatic BRCA mutation, and 20% a mutation in, or epigenetic silencing of, another homologous recombination gene [20], [21]. These tumours are thus subjected to the effect of a series of drugs whose mechanism of action interferes with DNA repair mechanisms, in particular PARPis, that by exploiting the concept of “synthetic lethality” previously described, have greatly changed
Author contribution
Federica Tomao and Nicoletta Colombo are responsible for the initial conceptualization of the paper, coordination of the project and resolved disagreement between reviewers. Erlisa Bardhi, Anna Di Pinto and Carolina Maria Sassu are responsible for the search and collection of data. Federica Tomao and Elena Biagioli are responsible for analysis of data. Erlisa Bardhi, Anna Di Pinto, Carolina Maria Sassu, are responsible for writing and editing the manuscript. Maria Cristina Petrella revised the
Declaration of Competing Interest
None.
References (29)
- et al.
Homologous recombination deficiency and ovarian cancer
Eur J Cancer
(2016) - et al.
What is the place of PARP inhibitors in ovarian cancer treatment?
Curr Oncol Rep
(2016) - et al.
Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial
Lancet Oncol
(2015) - et al.
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias
J Craniomaxillofac Surg
(2011) - et al.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial
Lancet Oncol
(2014) - et al.
Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a doubleblind, randomised, placebo-controlled, phase 3 trial
Lancet Oncol
(2017) - et al.
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet
(2017) - et al.
Rucaparib: An emerging parp inhibitor for treatment of recurrent ovarian cancer
Cancer Treat Rev
(2018) - et al.
Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma
Gynecol Oncol
(2012) - et al.
The Era of PARP inhibitors in ovarian cancer: “Class Action” or not? A systematic review and meta-analysis
Crit Rev OncolHematol
(2018)
Integrated genomic analyses of ovarian carcinoma
Nature
PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer
Cancer Chemother Pharmacol
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas
Clin Cancer Res
Niraparib in ovarian cancer: results to date and clinical potential
TherAdv Med Oncol.
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.