PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms

Abstract

Poly (ADP‐ribose) polymerase (PARP) inhibitors have provided great clinical benefits to ovarian cancer patients. To date, three PARP inhibitors, namely, olaparib, rucaparib and niraparib have been approved for the treatment of ovarian cancer in the United States. Homologous recombination deficiency (HRD) and platinum sensitivity are prospective biomarkers for predicting the response to PARP inhibitors in ovarian cancers. Preclinical data have focused on identifying the gene aberrations that might generate HRD and induce sensitivity to PARP inhibitors in vitro in cancer cell lines or in vivo in patient‐derived xenografts. Clinical trials have focused on genomic scar analysis to identify biomarkers for predicting the response to PARP inhibitors. Additionally, researchers have aimed to investigate mechanisms of resistance to PARP inhibitors and strategies to overcome this resistance. Combining PARP inhibitors with HR pathway inhibitors to extend the utility of PARP inhibitors to BRCA‐proficient tumours is increasingly foreseeable. Identifying the population of patients with the greatest potential benefit from PARP inhibitor therapy and the circumstances under which patients are no longer suited for PARP inhibitor therapy are important. Further studies are required in order to propose better strategies for overcoming resistance to PARP inhibitor therapy in ovarian cancers.

Phase I study of the PARP inhibitor talazoparib with radiation therapy for locally recurrent gynecologic cancers

“…Nevertheless, the overall response rate to PARP-inhibitors ranges from 30 to 50% [39], suggesting that a large population of patients have either de novo resistance or later develop drug resistance. While work has been done on developing biomarkers of response and resistance, these studies remain inconclusive and include a small number of patients [40]. To address this gap, this study will also aim to explore signatures of response and resistance using patient tumor biopsies to identify potential biomarkers for more accurate precision medicine.…”

PARP1 (poly(ADP-ribose) polymerase 1)

“…Breast Cancer Susceptibility Genes BRCA1 and BRCA2 are tumor suppressors that function in the repair DSBs via the homologous recombination (HR) repair pathway. In BRCA mutant tumor cells, PARP inhibition was shown to induce 'synthetic lethality' resulting in profound tumor cell cytotoxicity without harming normal cells (Jiang, Li, Li, Bai, Zhang, 2019). In addition to malignant tissues of BRCA-mutant, triple-negative, and receptor-positive breast carcinoma, PARP1 is overexpressed significantly in uterine carcinoma and ovarian carcinoma.…”

The mechanism of cancer cell death by PARP inhibitors goes beyond DNA damage alone

“…In clinical trials, the efficacy of PARP inhibitors has been mainly and firstly proven in the maintenance treatment after platinum‐based regimen response in BRCA‐mutated ovarian cancer . However, a significant benefit has been obtained also in non‐BRCA‐mutated platinum‐sensitive and, even lower, in a small sample of platinum‐resistant ovarian cancer patients .…”

“…In clinical trials, the efficacy of PARP inhibitors has been mainly and firstly proven in the maintenance treatment after platinum‐based regimen response in BRCA‐mutated ovarian cancer . However, a significant benefit has been obtained also in non‐BRCA‐mutated platinum‐sensitive and, even lower, in a small sample of platinum‐resistant ovarian cancer patients . To date, the clinical research on the therapeutic role of these drugs in other cancer types has gained importance and PARP inhibitors demonstrated efficacy against breast, gastric and lung cancer both in monotherapy and in combination.…”