PARP inhibition and synthetic lethality in ovarian cancer

Abstract

Ovarian cancer is the leading cause of gynecologic cancer death in women. Our understanding of the treatment of ovarian cancer has evolved over the last decade, with the use neo-adjuvant chemotherapy, combined intravenous-intraperitoneal (IV-IP) chemotherapy, as well as dose dense paclitaxel. Despite significant improvements in overall survival, the majority of patients succumb to recurrent chemotherapy resistant disease. Given the above, an emphasis has been placed on exploring alternate therapeutics. Recent research efforts have improved our understanding of the molecular biology of ovarian cancer and novel targeted treatment strategies have emerged. With the discovery of BRCA1 and BRCA2 gene mutations, and a more comprehensive assessment of heredity ovarian cancer syndrome, targeted interventions exploiting this biologic susceptibility have emerged. To date, the most studied of these have been PARP inhibitors. The purpose of this review will be to discuss PARP inhibition in advanced stage ovarian cancer, highlighting recent scientific advancements.

Keywords::

• cancer
• inhibition
• lethality
• ovarian
• PARP

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Homologous recombination deficiency is estimated to occur in up to 24% of patients with advanced stage ovarian cancer.

• Poly-ADP ribose polymerase (PARP) inhibition has been identified as a novel therapeutic option in patients with homologous recombination deficiency.

• Current Phase II clinical trials show promising response rates with manageable toxicity profile.

• Three Phase III clinical trials are currently enrolling patients to study the impact of PARP inhibition on oncologic outcome.

• Moving forward, the identification of patients most likely to respond to PARP inhibition is critical, while working to identify mechanisms of acquired resistance.

• Additional research is needed to help expand our understanding of the contribution of non-BRCA mutations on homologous recombination and sensitivity to PARP inhibition.

Notes