Table 1.

Rationale underlying chemotherapy-sparing options in the treatment of recurrent ovarian cancer

Therapeutic strategy	Rationale
Monotherapy
PARP inhibitors	PARPs are a large family of 17 nucleoproteins with diverse functions, including in DNA repair, spurring the development of PARP inhibitors as cancer therapies.8 9 The inhibition of PARP enzymes causes single-strand breaks to persist and subsequent double-strand breaks to accumulate. While normal cells are able to repair double-strand breaks via homologous recombination repair, cancer cells with homologous recombination deficiency (such as loss-of-function BRCA mutations) are unable to repair double-strand breaks, resulting in the accumulation of DNA damage and cell death.10 11 Other mechanisms of PARP inhibitor activity have been described, such as PARP1 trapping, impaired BRCA1 recruitment, and activation of non-homologous end joining.12 13
Immunotherapy	The presence of TIL in the tumor microenvironment, detected in around 50% of ovarian cancers, has been associated with a survival benefit, regardless of tumor grade, stage, or histologic subtype.31 32 However, several factors in the tumor microenvironment counteract the activity of TIL, generating immune escape mechanisms that enable cancer progression.33–38 Blocking these inhibitory signals with checkpoint inhibitors allows restoration of the anti-tumor activity of effector T-cells and mediates tumor regression.39
Dual combination therapy
PARP inhibitors with anti-angiogenic agents	PARP inhibition decreases angiogenesis and may prevent accumulation of HIF1, which is involved in the acquisition of resistance to angiogenesis inhibitors.57 Additionally, VEGFR inhibition can affect homologous recombination DNA repair, by downregulating BRCA1/2 and RAD51, and simultaneously suppress angiogenesis, increasing the anti-tumor activity of PARP inhibitors.58
PARP inhibitors with immunotherapy	Homologous recombination-deficient cells have error-prone DNA repair mechanisms, leading to somatic mutations that can result in neoantigen formation and immune system activation.49 On the other hand, BRCA-mutated and homologous recombination-deficient ovarian cancers also have increased CD3+and CD8+ immune cell infiltration compared with homologous recombination-proficient tumors.50 Another mechanism by which defective DNA repair can lead to immune activation is by release of damaged DNA resulting in activation of the innate immune system. The cGAS-STING pathway is a major mechanism of the innate immune system, which protects cells from cytosolic DNA derived from any source, including viruses and tumor cells. The anti-tumor efficacy of PARP inhibition is dependent on STING pathway activation. In mouse models, PARP inhibition with olaparib triggered robust anti-tumor activity that was diminished by loss of cytotoxic T-cells or loss of STING pathway signaling in BRCA-deficient51 as well as BRCA-wild type models.52 This body of evidence suggested that, by interfering with homologous recombination repair, PARP inhibitors could increase neoantigen production and stimulate the tumor immune microenvironment to synergize with checkpoint inhibitors.
Anti-angiogenic agents with immunotherapy	Angiogenic factors like VEGF are key regulators of physiological and pathological angiogenesis and play a major role in tumorigenesis.58 VEGF is highly expressed in the tumor microenvironment of ovarian cancer,59 promoting tumor angiogenesis, favoring peritoneal dissemination of ovarian cancer through malignant ascites formation, and enhancing vascular permeability.60 In addition, VEGF creates an immunosuppressive environment through release of inhibitory cytokines and recruitment of immunosuppressive cells.61 This provided the rationale for the combined targeting of angiogenesis and immune checkpoints as a way of reversing immunosuppression mediated by VEGF and thus increasing the efficacy of checkpoint inhibitors in ovarian cancer.

BRCA, BReast CAncer gene; CD, cluster of differentiation; DNA, deoxyribonucleic acid; HIF1, hypoxia inducible factor 1 alpha; PARP, poly-ADP ribose polymerase; cGAS-STING pathway, cyclic GMP-AMP synthase-stimulator of interferon genes pathway; TIL, tumor-infiltrating lymphocyte; VEGFR, vascular endothelial growth factor receptor.