title: Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Cancer Therapy Evaluation Program , National Cancer Institute , Bethesda , MD , USA.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: b Gynecologic Oncology Program , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: c Center for Cancer Research , National Cancer Institute , Bethesda , MD , USA.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: b Gynecologic Oncology Program , Dana-Farber Cancer Institute , Boston , MA , USA.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: a Cancer Therapy Evaluation Program , National Cancer Institute , Bethesda , MD , USA.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010793:Phthalazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles; C531550:olaparib
keywords: DNA repair defect; Germline deleterious BRCA1/2 mutation; chemical and contextual synthetic lethality; high grade serous ovarian cancer; homologous recombination repair; poly(adenosine diphosphate-ribose) polymerase inhibitor; vascular endothelial growth factor receptor inhibitor