Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

Keywords: DNA repair; PARP inhibitor; combinations; homologous recombination; ovarian cancer.

Figure 1

PARP inhibitor resistant mechanism and rationale for combinations. Although homologous recombination restoration due to secondary somatic reverse mutations is well-described as a possible resistance mechanism to PARP inhibitors, many other alterations are also possibly implied. The figure illustrates PARP inhibitor resistant mechanisms and the rationale for combinations currently under investigation in ovarian cancer. Additional blockade of DNA repair may be achieved through targeting other proteins involved in DNA repair, modifying cross-talking pathways to result in a contextual homologous recombination deficiency, and impairing the cell cycle. The following resistant mechanisms are represented: 1) BRCA reversion mutations and homologous recombination restoration; 2) Loss of 53BP1 expression and non-homologous end-joining impairment; 3) Stabilization of stalled fork and cell cycle regulation; 4) PI3K/AKT and other pathogenic pathways activation; 5) MDR1 overexpression; 6) PARP1 mutation or loss of expression. HR, homologous recombination; NHEJ, non-homologous end-joining; PARP, poly (ADP-ribose) polymerase; MDR1, multidrug resistance protein 1.

Figure 2

PARP inhibitor combination with cytotoxic agents and immunotherapy. The figure illustrates the rationale for combining PARP inhibitors with DNA damaging agents (A) and immunotherapy (B). DNA damaging agents such as cytotoxic chemotherapy and radiotherapy increase DNA damage, when DNA repair is impaired by the PARP inhibitor. The addition of immune checkpoint inhibitors to the PARP inhibitor can potentially optimize anti-tumor immune response. PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death-ligand 1; PD-1, programmed cell death protein 1; CTLA4, cytotoxic T-lymphocyte associated protein 4.