Olaparib
Encyclopedia
Olaparib is a chemotherapeutic agent developed by KuDOS Pharmaceuticals and later by Astra Zeneca. It is an inhibitor
of PARP, an enzyme involved in DNA repair
. It acts against cancers in people with hereditary BRCA1
or BRCA2
mutations, which includes many ovarian, breast and prostate cancers. Early (Phase I) trials have been promising, and it is now in Phase II trials, but is not clinically approved.
Poly ADP ribose polymerase
(PARP) and is one of the first PARP inhibitor
s. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers 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 significant benefit in patients whose cancers are susceptible to this treatment.
In one of these studies, it was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancer
s caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised. One of the first patients to be given the treatment (who had castration-resistant prostate cancer) was still in remission after two years.
Phase II clinical trials are ongoing in breast, ovarian and colorectal cancer. A phase II trial that included 63 cases of ovarian cancer concluded that olaparib is promising for women with ovarian cancer. [7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.]
, nausea
, loss of appetite and thrombocytopenia
.
PARP inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
of PARP, an enzyme involved in DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
. It acts against cancers in people with hereditary BRCA1
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...
or BRCA2
BRCA2
BRCA2 is a protein that in humans is encoded by the BRCA2 gene.BRCA2 orthologs have been identified in most mammals for which complete genome data are available....
mutations, which includes many ovarian, breast and prostate cancers. Early (Phase I) trials have been promising, and it is now in Phase II trials, but is not clinically approved.
Mechanism of action
Olaparib acts as an inhibitor of the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
Poly ADP ribose polymerase
Poly ADP ribose polymerase
Poly polymerase is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.-Members of PARP family:The PARP family comprises 17 members...
(PARP) and is one of the first PARP inhibitor
PARP inhibitor
PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase . They are developed for multiple indications; the most important is the treatment of cancer...
s. Patients with BRCA1/2 mutations may be genetically predisposed to developing some forms of cancer, and are often resistant to other forms of cancer treatment, but this also sometimes gives their cancers 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 significant benefit in patients whose cancers are susceptible to this treatment.
Trial results
Phase I clinical trials, in patients with BRCA-mutated tumors including ovarian cancer, were encouraging.In one of these studies, it was given to 19 patients with inherited forms of advanced breast, ovarian and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
s caused by mutations of the BRCA1 and BRCA2 genes. In 12 of the patients, none of whom had responded to other therapies, tumours shrank or stabilised. One of the first patients to be given the treatment (who had castration-resistant prostate cancer) was still in remission after two years.
Phase II clinical trials are ongoing in breast, ovarian and colorectal cancer. A phase II trial that included 63 cases of ovarian cancer concluded that olaparib is promising for women with ovarian cancer. [7 responses in 17 patients with BRCA1 or BRCA2 mutations and 11 responses in the 46 who did not have these mutations.]
Side effects
Olaparib is generally well tolerated, the side effects consist mainly of fatigue, somnolenceSomnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, loss of appetite and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
.