Abstract
Simple SummaryPARP inhibitors are a class of orally active drugs that kill a range of cancer types by inducing synthetic lethality. The usefulness of PARP inhibitors for the treatment of haematological malignancies has begun to be explored in a variety of both pre-clinical models and human clinical trials. Despite being largely considered safe and well tolerated, secondary haematological malignancies have arisen in patients following treatment with PARP inhibitors, raising concerns about their use. In this review, we discuss the potential benefits and risks for using PARP inhibitors as treatments for haematological malignancies.Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with BRCA gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though BRCA mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is required. Paradoxically, secondary haematological malignancies have arisen in patients after treatment with PARPi, raising concerns about their potential use as therapies for any blood or bone marrow-related disorders. Here, we provide a comprehensive review of the biological, pre-clinical, and clinical evidence for and against treating individual haematological malignancies with approved and experimental PARPi. We conclude that the promise of effective treatment still exists, but remains limited by the lack of investigation into useful biomarkers unique to these malignancies.
Highlights
Cells are frequently subjected to DNA damage from a variety of endogenous and exogenous reactive molecules and insults
A large meta-analysis (n = 12 trials; 5347 patients) demonstrated that PARPi significantly improve progression-free survival (PFS) and overall response rate (ORR) compared to placebo and chemotherapies [145], and a second meta-analysis of olaparib, niraparib and rucaparib (n = 6 trials; 2270 patients) demonstrated that there are no significant differences in clinical outcomes (OS or PFS) between these three PARPi [146], and together these analyses highlight why PARPi are considered to be the drug of choice in maintenance therapy for platinum-sensitive ovarian cancer
A larger meta-analysis and retrospective pharmacovigilance study examining 18 placebo and 10 non-placebo randomised control trials (RCTs) and 211 cases in the World Health Organisation (WHO) pharmacovigilance database (VigiBase) demonstrated that PARPi increase the risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemias (AML) when compared to placebo treatment (Peto OR 2.63, 95% CI 1.13–6.14)
Summary
Cells are frequently subjected to DNA damage from a variety of endogenous and exogenous reactive molecules and insults. Numerous studies have suggested that cancer progression involves selection of sub-clones with additional mutations that allow them to grow and survive [1] This clonal evolution is enabled by genomic instability, whereby cells continuously accumulate mutations following DNA damage [2] and is exacerbated by defects in the DNA damage response. PARPi variety of haematological [5] This highlights how critical it is to better understand the risk of PARPi treatment for difsafe and well tolerated, alarmingly, a small but significant portion of patients with solid ferent types of cancer before potential use for haematological tumours treated clinically withinvestigating. Highlights how critical it is to better understand the risk of PARPi treatment for different types of cancer before investigating its potential use for haematological malignancies
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