Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system

Abstract

High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.

Keywords: PARPi combinations; checkpoint inhibition; clinical trials; combination (combined) therapy; epigenetics; high-grade serous ovarian carcinoma; immunotherapy; poly ADP-ribose polymerase inhibitors.

FIGURE 1

Characteristics, initiation, and molecular progression of HGSOC. (A) Most common mutations include ubiquitous loss of TP53 (96.7% of cases), loss of BRCA1/2 (somatic/germline mutations, promoter methylation), CCNE1 amplification, NF1, RB1 and PTEN mutations. (B) The loss of TP53 is thought to be the initiating event that with subsequent loss of HR pathways stimulates the chromosomal instability and widespread copy number changes seen in HGSOC. This causes changes in gene expression and promotes the development of specific molecular changes that define the 4 HGSOC subtypes (C1, C2, C4, and C5). Loss of HR, specifically BRCA1, can elicit immune responses through increased neoantigen loads and upregulation of inflammatory pathways. Additionally, HRD and BRCA mutant tumours have been associated with elevated levels of TILs. Common immune evasion mechanisms that HGSOC develop to negate these innate immunogenic traits include the upregulation of immune checkpoints, overexpression of angiogenesis factor VEGF-A and the downregulation of immune-stimulating molecules.