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Trade names | Lynparza, others |
Other names | AZD-2281, MK-7339, KU0059436 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a614060 |
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Routes of administration | By mouth |
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ECHA InfoCard | 100.170.811 |
Chemical and physical data | |
Formula | C24H23FN4O3 |
Molar mass | 434.471 g·mol−1 |
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Olaparib, sold under the brand name Lynparza, is a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which include some ovarian, breast, and prostate cancers. [8]
In December 2014, olaparib was approved for use as a single agent by the European Medicines Agency (EMA) in the European Union and by the Food and Drug Administration (FDA) in the United States. [9] [10] [11] [12]
Olaparib is indicated to treat breast cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, pancreatic cancer, and prostate cancer. [6] [10] [13]
Side effects include gastrointestinal effects such as nausea, vomiting, and loss of appetite; fatigue; muscle and joint pain; and low blood counts such as anemia, with occasional leukemia. [5] Somnolence was sometimes seen in clinical trials which used doses higher than the approved schedule. [8]
Olaparib acts as an inhibitor of the enzyme poly ADP ribose polymerase (PARP), and is termed a PARP inhibitor. BRCA1/2 mutations may be genetically predisposed to development of some forms of cancer, and may be resistant to other forms of cancer treatment. However, these cancers sometimes have a unique vulnerability, as the cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs which selectively inhibit PARP may be of benefit if the cancers are susceptible to this treatment. [14] [15]
Olaparib was developed and first dosed into patients by the UK-based biotechnology company, KuDOS Pharmaceuticals, that was founded by Stephen Jackson of Cambridge University, UK. [16] [17] [18] [19] Since KuDOS was acquired by AstraZeneca in 2006, the drug has undergone clinical development by AstraZeneca and Merck & Co. [20]
In December 2014, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved olaparib as monotherapy. [5] [12] [11] [9] [10] The FDA approval is in germline BRCA mutated (gBRCAm) advanced ovarian cancer [21] that has received three or more prior lines of chemotherapy. [5] [22] The EMA public assessment report, which utilized the same phase II trial data, made reference to both "high grade serous ovarian cancers" and to the use of olaparib "not later than 8 weeks after a course of platinum-based medicines, when the tumour was diminishing in size or had completely disappeared". [9]
Olaparib in combination with temozolomide demonstrated substantial clinical activity in relapsed small cell lung cancer. [23]
The FDA approval was for germline BRCA mutated (gBRCAm) advanced ovarian cancer that has received three or more prior lines of chemotherapy. [5] In January 2018, olaparib became the first PARP inhibitor to be approved by the FDA for gBRCAm metastatic breast cancer.
In breast cancer, olaparib is approved for gBRCAm HER2-negative metastatic breast cancer patients who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. If patients have hormone receptor positive cancer, they should have received endocrine therapy where appropriate. [6] This approval was based on the OlympiAD randomised phase III trial, which showed a progression-free survival benefit for patients treated with olaparib compared to conventional chemotherapy. [24] [25]
In August 2017, olaparib tablets were approved in the United States for the maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. [26] [27] The formulation was changed from capsules to tablets and the capsules were phased out in the United States. [26] The capsules and tablets are not interchangeable. [26]
The approval in the maintenance setting was based on two randomized, placebo-controlled, double-blind, multicenter trials in patients with recurrent ovarian cancers who were in response to platinum-based therapy. [26] SOLO-2 (NCT01874353) randomized 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer (2:1) to receive olaparib tablets 300 mg orally twice daily or placebo. [26] SOLO-2 demonstrated a statistically significant improvement in investigator-assessed progression-free survival (PFS) in patients randomized to olaparib compared with those who received placebo, with a hazard ratio (HR) of 0.30 (95% CI: 0.22, 0.41; p<0.0001). [26] Study 19 (NCT00753545) randomized 265 patients regardless of BRCA status (1:1) to receive olaparib capsules 400 mg orally twice daily or placebo. [26] Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with olaparib vs. placebo with a HR of 0.35. [26]
In January 2018, olaparib was approved in the United States for the treatment of patients with certain types of breast cancer that have spread (metastasized) and whose tumors have a specific inherited (germline) genetic mutation, making it the first drug in its class (PARP inhibitor) approved to treat breast cancer, and it is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a “BRCA” gene mutation. [28] Patients are selected for treatment with Lynparza based on an FDA-approved genetic test, called the BRACAnalysis CDx. [28]
In December 2018, olaparib was approved in the United States for the maintenance treatment of adults with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. [29] Adults with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer should be selected for therapy based on an FDA-approved companion diagnostic. [29] Approval was based on SOLO-1 (NCT01844986), a randomized, double-blind, placebo-controlled, multi-center trial that compared the efficacy of olaparib with placebo in patients with BRCA-mutated (BRCAm) advanced ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy. [29] Patients were randomized (2:1) to receive olaparib tablets 300 mg orally twice daily (n=260) or placebo (n=131). [29]
In December 2019, olaparib was approved for the maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. [30] The FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with olaparib based upon the identification of deleterious or suspected deleterious germline mutations in BRCA1 or BRCA2 genes. [30] Efficacy was investigated in POLO (NCT02184195), a double-blind, placebo-controlled, multi-center trial that randomized (3:2) 154 patients with gBRCAm metastatic pancreatic adenocarcinoma to olaparib 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity. [30]
In March 2022, olaparib was approved for the adjuvant treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. [13]
In April 2023, the National Health Service (NHS) in Wales and England will administer Olaparib to cancer patients as part of its targeted therapy. This drug is developed to target specific malignancies connected to defective breast cancer (BRCA) gene variants. Through this move, 800 people—300 women with early breast cancer and 500 men with advanced prostate cancer will receive this drug for free. Andrew Tutt, a breast oncology professor at King's College London and Institute of Cancer Research said that this treatment increases patients’ chances of surviving breast cancer. It can also extend a person’s life in cases of prostate cancer. Tutt added that these were previously unattainable. [31]
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.
Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.
Cediranib is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases.
Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification. Triple-negative is sometimes used as a surrogate term for basal-like.
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP).
Veliparib (ABT-888) is a potential anti-cancer drug acting as a PARP inhibitor. It kills cancer cells by blocking a protein called PARP, thereby preventing the repair of DNA or genetic damage in cancer cells and possibly making them more susceptible to anticancer treatments. Veliparib may make whole brain radiation treatment work more effectively against brain metastases from NSCLC. It has been shown to potentiate the effects of many chemotherapeutics, and as such has been part of many combination clinical trials.
Rucaparib, sold under the brand name Rubraca, is a PARP inhibitor used as an anti-cancer agent. Rucaparib is a first-in-class pharmaceutical drug targeting the DNA repair enzyme poly-ADP ribose polymerase-1 (PARP-1). It is taken by mouth.
Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma and glioma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2. It is taken by mouth.
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.
Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib. It was developed by Array Biopharma.
Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).
Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.
Clovis Oncology is an American pharmaceutical company which mainly markets products for treatment in oncology. Clovis was founded in 2009 and is headquartered in Boulder, Colorado. The company is a publicly traded company on NASDAQ under the symbol CLVS and is in the NASDAQ Biotechnology Index with several products in its product pipeline. As of December 31, 2017, the company was not profitable and had incurred losses in each year since its inception in April 2009. In December 2022, Clovis Oncology filed for Chapter 11 bankruptcy.
Talazoparib, sold under the brand name Talzenna, is an anti-cancer medication used for the treatment of breast cancer and prostrate cancer. It is an orally available poly ADP ribose polymerase PARP inhibitor marketed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations. Talazoparib is similar to the first in class PARP inhibitor, olaparib.
Alpelisib, sold under the brand name Piqray among others, is a medication used to treat certain types of breast cancer. It is used together with fulvestrant. It is taken by mouth. It is marketed by Novartis.
Niraparib, sold under the brand name Zejula, is an anti-cancer medication used for the treatment of epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is taken by mouth. It is a PARP inhibitor.
HRDetect is a whole-genome sequencing (WGS)-based classifier designed to predict BRCA1 and BRCA2 deficiency based on six mutational signatures. Additionally, the classifier is able to identify similarities in mutational profiles of tumors to that of tumors with BRCA1 and BRCA2 defects, also known as BRCAness. This classifier can be applied to assess the implementation of PARP inhibitors in patients with BRCA1/BRCA2 deficiency. The final output is a probability of BRCA1/2 mutation.
Adagrasib, sold under the brand name Krazati, is an anticancer medication used to treat non-small cell lung cancer. Adagrasib is an inhibitor of the RAS GTPase family. It is taken by mouth. It is being developed by Mirati Therapeutics.
Niraparib/abiraterone acetate, sold under the brand name Akeega, is a fixed-dose combination anti-cancer medication used for the treatment of prostate cancer. It contains niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor.