Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: An updated systematic review and meta-analysis of randomized controlled trials

PARP Inhibitors and Haematological Malignancies—Friend or Foe?

“…A further meta-analysis examining the safety of maintenance therapy with olaparib after platinum-based chemotherapy in cancer patients ( n = 4 trials; 1099 patients with BRCA mutated advanced cancers) once again demonstrated that patients treated with maintenance olaparib showed higher risk of all-grade and high-grade anaemia, all-grade neutropaenia and thrombocytopaenia compared to the placebo group [ 152 ]. A larger review of phase II and III RCTs in ovarian cancer ( n = 10 trials; 4553 patients) confirmed these earlier findings and demonstrated that patients treated with PARPi exhibited slight to moderately higher risks of all-grade and high-grade haematological toxicities (including anaemia, leucopaenia, neutropaenia, and thrombocytopaenia with RR ranging from 1.42–3.49) and also marginally increased risks of all-grade gastrointestinal toxicities (including diarrhoea, nausea, vomiting, and constipation with RR ranging from 1.20–1.84) compared to control groups [ 148 ]. In addition, a recent large meta-analysis of 29 RCTs (9247 patients) showed that PARPi significantly increases the risk of all-grade anaemia, neutropaenia, and thrombocytopaenia (RR 1.69–2.52) compared to control groups [ 151 ]; however, this varied with treatment duration.…”

“…Similar survival benefits have also been observed for metastatic breast cancer [ 147 ]. Interestingly, these survival benefits have been identified irrespective of BRCA mutation status [ 148 , 149 ]. However, despite these demonstrated survival benefits, concerning haematological toxicities have been observed across a number of studies, which has raised concern as to the suitability of the continued use of these PARPi.…”

“…To help address this controversy, several systematic reviews and meta-analyses have been conducted to evaluate incidence rates and risk ratios for these toxicities in a range of cancer types [ 145 , 146 , 148 , 150 , 151 , 152 ]. A review of olaparib, veliparib and niraparib phase II and III randomised control trials (RCTs) in ovarian, gastric, non-small-cell lung, and breast cancer and melanoma patients ( n = 12 trials; 2479 patients) identified that PARPi treatment significantly more than doubled the relative risk (RR) of severe neutropaenia, thrombocytopaenia, and anaemia, when compared to control groups [ 150 ].…”

Utilization of Poly(ADP-Ribose) Polymerase Inhibitors in Ovarian Cancer: A Retrospective Cohort Study of US Healthcare Claims Data

“…Hematologic toxicities are a common class effect of PARPi, often occurring early after treatment initiation; they are also the most common cause of dose modification, interruption, and discontinuation [4]. In our Highest indicated doses were taken from the prescribing information for each PARPi as 600, 800, 300, and 1200 mg/day for olaparib tablets, olaparib capsules, niraparib capsules, and rucaparib tablets, respectively c Days to non-persistence were determined among the subset of patients who had at least 6 months of follow-up; persistence was indicated by no treatment gaps of more than 90 days during the 6-month post-index period [21] d MPR was measured as the ratio of the sum of days' supply during the fixed 6-month (180-day) follow-up period among the subset of patients with at least 6 months of follow-up [21] study, rates of hematologic CEIs were consistent with RCT data [7,8] and were higher with niraparib, followed by rucaparib and then olaparib. Differences between PARPi in terms of tolerability and dose modifications in pivotal RCTs in the OC maintenance setting have recently been highlighted in an indirect treatment comparison [18].…”

Upregulated SPOCK2 Predicts a Worse Overall Survival and Correlates with Abundance of Tumor Infiltrating Immune Cells for High-Grade Serous Ovarian Cancer

“…In addition to systemic therapy that maximizes the effect of killing cancer cells in a platinumsensitive setting, poly (ADP-ribose) polymerase inhibitors (PARPi) have presented remarkable bene t in women with recurrent HGSOC regardless of BRCA mutation status, by contrast with improved activity in patients harboring BRCA mutations and platinum-sensitive disease (González-Martín et al 2019; Mirza et al 2016;Oza et al 2018). Nevertheless, multiple acquired resistance mechanisms to PARPi and potential drug toxicities have retarded clinical e cacy, suggesting that efforts might be leveraged into novel researches to delineate resistance mechanisms, prompt drug responses, or nd new and speci c prognostic biomarkers and therapeutic targets (Hao et al 2021; Kubalanza and Konecny 2020). SPARC (osteonectin), cwcv and kazal-like domains proteoglycan 2 (SPOCK2), also known as testican-2, is a member of the SPARC family composing of FSTL1, SMOC1, SMOC2, SPARC, SPARCL1, SPOCK1, SPOCK2, and SPOCK3 (Bradshaw et al 2012;Said et al 2008).…”