Abstract
Inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers.
Highlights
Each year, over 1 million women worldwide are newly diagnosed with gynecologic malignancy, and almost 500,000 women will die from gynecologic cancer [1]
Options in Oncol. (2016) 17: 12 role of PARP inhibitors (PARPi) is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for homologous recombination-deficient (HRD) may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD
The last decade of research in the treatment of gynecologic cancers has seen the development of multimodal options, including anti-angiogenic biologics, like bevacizumab, and targeted therapies, like olaparib, a PARPi recently approved for the fourth-line treatment of BRCA-deficient ovarian cancers
Summary
Over 1 million women worldwide are newly diagnosed with gynecologic malignancy, and almost 500,000 women will die from gynecologic cancer [1]. PARP inhibitors have the benefit of being an oral medication which minimizes the impact on quality of life for patients with recurrent cancer. The significant clinical impact of PARP inhibition, a manifestation of sound translational rationale behind therapeutic development, can be attributed to the exploitation of synthetic lethality as a mechanism that selectively targets a specific population of cancer cells, those deficient in tumor suppressor genes BRCA 1 and BRCA 2. The purpose of this article is to provide a background on synthetic lethality, an overview of clinical trials investigating the use of PARPi in gynecologic cancers, highlighting the approval of olaparib in the treatment of recurrent BRCAdeficient ovarian cancer, and identification of patients with a homologous recombination-deficient (HRD) profile to better tailor treatment of women with gynecologic cancers in the future (Table 1)
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