Ovary
General
Olaparib
Author: Y. Albert Yeh, M.D., Ph.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Last author update: 19 May 2020
Last staff update: 28 June 2021
Copyright: 2020-2024, PathologyOutlines.com, Inc.
PubMed Search: Olaparib[TI] pathology free full text[sb]
Table of Contents
Definition / general | Trade name | Indications | Pathophysiology | Diagrams / tables | Clinical information | Uses by pathologists | Side effects | Drug administration | Additional references | Board review style question #1 | Board review style answer #1Cite this page: Yeh YA. Olaparib. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovaryolaparib.html. Accessed May 13th, 2024.
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
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
- Positive BRCA1 mutation if < 10% nuclear staining ovarian carcinoma cells (J Clin Pathol 2020;73:191)
- 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
Additional references
- J Adv Pract Oncol 2019;10:167, Cells 2019;8:E860, Curr Treat Options Oncol 2018;19:21, Curr Treat Options Oncol 2018;19:1, Genes Dev 2020;34:360, Mol Cancer 2020;19:49, Nature 2012;481:287, N Engl J Med 2012;366:1382, N Engl J Med 2015;373:1697, N Engl J Med 2018;379:2495, N Engl J Med 2019;381:2416, Pancreas (Fairfax) 2019;3:e5
Board review style question #1
Which of the following is true about olaparib?
- Olaparib is used to treat breast and ovarian cancers with BRAF mutation
- Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation
- Olaparib is used to treat breast and ovarian cancers with HER2 mutation
- Olaparib is used to treat breast and ovarian cancers with RAS mutation
Board review style answer #1
B. Olaparib is used to treat breast and ovarian cancers with BRCA1/2 mutation
Comment Here
Reference: Olaparib
Comment Here
Reference: Olaparib
