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Olaparib


Topic Completed: 19 May 2020

Minor changes: 19 May 2020

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PubMed Search: Olaparib[TI] pathology free full text[sb]

Y. Albert Yeh, M.D., Ph.D.
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Cite this page: Yeh YA. Olaparib. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/drugsolaparib.html. Accessed August 10th, 2020.
Definition / general
  • Apoly (ADP-ribose) polymerase (PARP) inhibitor blocks PARP1, PARP2, PARP3, which are involved in DNA transcription and DNA repair
  • Developed by KuDOS Pharmaceuticals and acquired and developed later by AstraZeneca Pharmaceuticals LP and Merck & Co
  • Synonym: AZD2281, MK-7339, Lynparza, PARP inhibitor AZD2281
Trade name
  • Lynparza®
Indications
  • Advanced ovarian cancer with BRCA1 and BRCA2 germ line mutations, has been treated with other types of chemotherapy (U.S. FDA approved, 12/19/2014) (Drugs.com: Olaparib [Accessed 5 May 2020])
  • Previously treated or metastatic breast cancer that is HER2 negative and has germ line mutations in BRCA1 and BRCA2 genes (U.S. FDA approved, 1/12/2018)
  • Advanced or recurrent ovarian epithelial, fallopian tube or primary peritoneal cancer with germ line / somatic mutations in BRCA1 and BRCA2 genes and partial or complete response to platinum chemotherapy (U.S. FDA approved, 12/9/2018)
  • Metastatic pancreatic cancer with germ line mutations in BRCA1 and BRCA2 genes and has been treated with platinum chemotherapy (U.S. FDA approved, 12/27/2019)
  • Reference: National Cancer Institute: Cancer Drugs [Accessed 5 May 2020]
Pathophysiology
  • In normal cells, base excision repair and homologous recombination mediated double strand breaks repair responsible for damaged DNA repair (Figure 1, panel A)
  • In cells with BRCA1 or BRCA2 mutation, base excision repair and other DNA repair systems compensate for the nonfunctional homologous recombination (Figure 1, panel B)
  • In cells with nonfunctioning base excision repair because of PARP1 inhibition and at least one copy of BRCA1 and BRCA2, homologous recombination can repair the DNA (Figure 1, panel C)
  • In cancer cells with BRCA1 or BRCA2 mutation, PARP1 inhibitor (olaparib) blocks the base excision repair leading to cell death (Figure 1, panel D)
  • Mechanism of drug resistance (Ann Oncol 2019;30:1437)
    • Secondary mutations resulting in somatic reversion or restoration of open reading frame of homologous recombination genes including BRCA1/2
    • Expression of functional hypomorphic variants of BRCA1/2
    • Stabilization of BRCA1/2 variants by HSP90
    • Reversion of BRCA1 epigenetic silencing by demethylation process
    • Removal of barriers to DNA end resection via loss of 53BP1 or proteins from shieldin complex
    • Oncogenic signaling that promotes expression of homologous recombination repair genes
    • Protection of the replication fork and decrease in cell cycle progression
  • Reference: N Engl J Med 2009;361:189, see diagram below
Diagrams / tables

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Mechanism of PARP1 inhibitor in cancer cells

Clinical information
  • BRCA1/2 aberrations occur in ovarian and breast cancers and 5% of other cancers including prostate, skin (nonmelanoma), endometrial, pancreatic and biliary duct cancers (Ann Oncol 2019;30:1437)
  • Efficacy of olaparib in BRCA mutated advanced ovarian cancer with prior treatment: objective response rate 34%, complete response 2%, partial response 32% (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
  • Efficacy in BRCA1/2 mutated HER2 negative metastatic breast cancer: objective response rate 52% (olaparib) versus 23% (nonolaparib chemotherapy)
  • Olaparib in patients with metastatic castration resistant prostate cancer with DNA repair gene aberrations: TOPARP-B, phase II clinical trial (Lancet Oncol 2020;21:162)
    • 161 of 711 patients with DNA damage repair gene aberrations
    • Decrease in PSA of 50%: 37% of patients received 400 mg; 30.2% with 300 mg
    • Circulating tumor cell count conversion: 53.6% of patients received 400 mg; 48.1% with 300 mg
  • Olaparib in patients with metastatic castration resistant prostate cancer with BRCA1/2 or ATM mutations: PROfound, phase III trial (Cancer Discov 2019;9:1638)
    • 245 patients with BRCA1/2 or ATM mutations
    • Objective response rate of 33.3% compared with 2.3% of patients who received enzalutamide or abiraterone plus prednisone
  • Restored DNA repair capacities found in resistant clones of carcinoma cells (Clin Cancer Res 2013;19:5485)
  • Myelodysplastic syndrome / acute myeloid leukemia occurred in < 1.5% with fatal outcome; discontinue if it is confirmed (Gynecol Oncol 2018;151:190)
  • Pneumonitis occurred in < 1% with some fatal outcome; discontinue if it occurs (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
  • Embryo / fetal toxicity: potential hazard to a fetus
  • Clinical pharmacokinetics (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
    • Absorption: rapid, peak median plasma concentrations peak at 1.5 hours after dosing, co-administration of a high fat meal slowed the rate
    • Distribution:
      • Mean volume of distribution 158 ± 136 L after a single dose of 300 mg
      • In vitro protein binding approximately 82%
    • Metabolism: mainly by CYP3A4/5 in vitro
    • Excretion: 44% via urine and 42% via feces
      • Mean terminal plasma half life of 14.9 ± 8.2 hours
      • Plasma clearance of 7.4 ± 3.9 L/h, after a single dose of 300 mg
  • Drug interactions: avoid concurrent use of strong or moderate CYP3A inhibitors such as itraconazole, clarithromycin, ketoconazole, ritonavir, indinavir, ciprofloxacin, diltiazem, erythromycin, fluconazole (FDA: LYNPARZA (Olaparib) Tablets [Accessed 6 May 2020])
  • Olaparib costs about $3,000 per month
Uses by pathologists
  • Anti-BRCA1 mouse monoclonal clone MS110, most effective antibody to detect mutated BRCA1
  • Normal BRCA1: retained BRCA1 staining
  • Abnormal BRCA1: equivocal and loss of BRCA1 staining (Am J Surg Pathol 2013;37:138)
Side effects
  • Anemia
  • Nausea
  • Vomiting
  • Diarrhea
  • Stomatitis
  • Infections and infestations
  • Nasopharyngitis / sinusitis / rhinitis / influenza
  • Fatigue including asthenia
  • Metabolism and nutrition disorders
  • Decreased appetite
  • Arthralgia / myalgia
  • Dysgeusia
  • Headache
  • Neutropenia
  • Reference: N Engl J Med 2009;361:123
Drug administration
  • 300 mg taken orally, twice daily for 2 years of treatment
  • Continued treatment until disease progression or intolerable drug toxicity
Board review style question #1
Which of the following is true about olaparib?

  1. Olaparib is used to treat breast and ovarian cancers with BRAF mutation
  2. Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation
  3. Olaparib is used to treat breast and ovarian cancers with HER2 mutation
  4. Olaparib is used to treat breast and ovarian cancers with RAS mutation
Board review answer #1
B. Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation

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Reference: Olaparib
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