Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer

ABSTRACT

Introduction: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC.

Areas covered: Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts.

Expert opinion: Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

KEYWORDS:

• Germline deleterious BRCA1/2 mutation
• chemical and contextual synthetic lethality
• poly(adenosine diphosphate-ribose) polymerase inhibitor
• DNA repair defect
• homologous recombination repair
• high grade serous ovarian cancer
• vascular endothelial growth factor receptor inhibitor

Box 2. Drug summary box

Box 1. PARP inhibitors (PARPi) in clinical development

Acknowledgments

The authors thank Kristie Magee, Technical Resources International, for her editorial and formatting help and Melissa Maher, Technical Resources International, for her help with the preparation of figures.

Declaration of interest

This paper has been supported by the National Cancer Institute, Bethesda, and Harvard Medical School, Boston. JD Liu is a consultant for AstraZeneca and Genentech, and has acted as principal investigator for clinical trials sponsored by AstraZeneca, Genentech, Merrimack Pharmaceuticals, Boston Biomedical and Atara Pharmaceuticals. U Matulonis has participated in advisory boards for AstraZeneca and Tesaro. The authors have no other 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.