title: Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.
abstract: BACKGROUND
  Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality.
  
  
  METHODS
  This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group.
  
  
  CONCLUSIONS
  Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study.
  
  
  CONCLUSIONS
  Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.
authors.affiliation: New York University, Perlmutter Cancer Center, New York, New York, USA Lawrence.Leichman@nyumc.org.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Leichman
authors.affiliation: University of Southern California, Norris Cancer Center, Los Angeles, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Wells
authors.initials: W
authors.lastname: Messersmith
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: New York University, Perlmutter Cancer Center, New York, New York, USA.
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Leichman
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Cohen
authors.affiliation: New York University, Perlmutter Cancer Center, New York, New York, USA.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Cohen
authors.affiliation: University of Southern California, Norris Cancer Center, Los Angeles, California, USA.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: Swedish Cancer Institute, Seattle, Washington, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Gold
authors.affiliation: Helen F. Graham Cancer Center and Research Institute, Newark, Deleware, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Boman
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
authors.affiliation: AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Gershon
authors.initials: G
authors.lastname: Locker
authors.affiliation: University of Texas MD Anderson Cancer, Houston, Texas, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Cason
authors.affiliation: University of Texas MD Anderson Cancer, Houston, Texas, USA.
authors.forename: Stan R
authors.initials: SR
authors.lastname: Hamilton
authors.affiliation: Yale University Cancer Center, New Haven, Connecticut, USA.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects; D053843:DNA Mismatch Repair / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability / Q000187:drug effects*; D008875:Middle Aged; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: Colon cancer; PARP inhibitor