New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors

• Published in: Current treatment options in oncology 2016-03, Vol.17 (3), p.12-12, Article 12
• Main Authors: Liu, Fong W., Tewari, Krishnansu S.
• Format: Article
• Language: English
• Subjects: BRCA1 Protein - genetics; BRCA2 Protein - genetics; Disease-Free Survival; DNA Repair - drug effects; Female; Genital Neoplasms, Female - drug therapy; Genital Neoplasms, Female - genetics; Genital Neoplasms, Female - pathology; Gynecologic Cancers (RJ Morgan; Homologous Recombination - genetics; Humans; Medicine; Medicine & Public Health; Oncology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Phthalazines - administration & dosage; Piperazines - administration & dosage; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerases - drug effects; Section Editor; Synthetic Lethal Mutations - genetics; Topical Collection on Gynecologic Cancers
• ISSN: 1527-2729; 1534-6277; 1534-5277
• DOI: 10.1007/s11864-015-0378-9

Opinion statement 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.