Abiraterone
Encyclopedia
Abiraterone is a drug used in castration-resistant prostate cancer (formerly hormone-resistant or hormone-refractory prostate cancer) (prostate cancer not responding to androgen deprivation or treatment with antiandrogen
s). It is formulated as the prodrug
abiraterone acetate and sold under the trade name Zytiga. After an expedited six-month review, abiraterone was approved by the U.S. Food and Drug Administration
(FDA) in April 2011. In Phase III trials, it extended median survival to 14.8 months versus 11.2 months placebo, and the trial was stopped because of the successful outcome.
Centre for Cancer Therapeutics at the Institute of Cancer Research
in London. Rights for commercialisation of the drug were assigned to BTG plc, a UK company that manages commercialisation activity in pharmaceuticals. BTG then licenced the product to Cougar Biotechnology which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson
which is currently conducting clinical trial
s on abiraterone.
, respectively, by its C17,20 lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone
.
(>99%), and is metabolised in the liver by CYP3A4
and SULT2A1
to inactive metabolites. The drug is excreted by feces (~88%) and urine (~5%) with a terminal half life of 12 ± 5 hours.
In September 2010, an independent panel found that the interim results of the phase III clinical trial in previously treated docetaxel patients were so successful that it would have been unethical to keep half the trial participants on placebo, and all patients began receiving the drug. Overall survival was increased by 3.9 months according to this trial. It was approved by the FDA in April 2011 .
The first clinical studies were run by Cancer Research UK's Drug Development Office at the Royal Marsden Hospital, London, and reported in 2004 . A more recent study at the Royal Marsden Hospital, London, in patients who had not received chemotherapy reported in 2007 that abiraterone acetate induced decline in prostate specific antigen
(PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, normalisation of lactate dehydrogenase. However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.
Results of two phase II trials indicate that abiraterone may reduce prostate specific antigen
(PSA) levels, as well as shrink tumors. Many of the 21 men in the Phase II trial reported significant improvements in their quality of life and several were able to stop taking morphine, used to control the pain caused after the cancer spread into their bones. On average, progression-free survival (PFS) was prolonged by 161 days in patients which had been treated with chemotherapy, and by 236 days in chemotherapy naive patients. Phase II clinical trials of abiraterone's effectiveness in patients who have not yet received treatment with chemotherapy (33 patients) found a median time to PSA progression of 48 weeks. Another phase II trial in patients who had failed prior treatment with docetaxel (47 patients) showed a median time to PSA progression of 24 weeks.
A phase I/II clinical trial evaluating abiraterone acetate in advanced breast cancer
patients is also underway, run by Cancer Research UK's Drug Development Office.
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
s). It is formulated as the prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
abiraterone acetate and sold under the trade name Zytiga. After an expedited six-month review, abiraterone was approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in April 2011. In Phase III trials, it extended median survival to 14.8 months versus 11.2 months placebo, and the trial was stopped because of the successful outcome.
History
This drug was initially discovered in the Cancer Research UKCancer Research UK
Cancer Research UK is a cancer research and awareness charity in the United Kingdom, formed on 4 February 2002 by the merger of The Cancer Research Campaign and the Imperial Cancer Research Fund. Its aim is to reduce the number of deaths from cancer. As the world's largest independent cancer...
Centre for Cancer Therapeutics at the Institute of Cancer Research
Institute of Cancer Research
The Institute of Cancer Research is a cancer research institute located in London, United Kingdom and a constituent college of the federal University of London. The ICR was founded in 1909 as a research department of the Royal Marsden Hospital and joined the University of London in 2003...
in London. Rights for commercialisation of the drug were assigned to BTG plc, a UK company that manages commercialisation activity in pharmaceuticals. BTG then licenced the product to Cougar Biotechnology which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson
Johnson & Johnson
Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....
which is currently conducting clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s on abiraterone.
Mechanism of action
Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedioneAndrostenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
, respectively, by its C17,20 lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
.
Pharmacokinetics
After oral administration, abiraterone acetate, the prodrug form present in the commercial preparation, is converted into the active form, abiraterone; this conversion is likely to be esterase-mediated and not CYP-mediated. Administration with food increases absorption of the drug and thus has the potential to result in increased and highly variable exposures; the drug should be consumed in empty stomach. The drug is highly protein boundPlasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...
(>99%), and is metabolised in the liver by CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
and SULT2A1
SULT2A1
Alcohol sulfotransferase is an enzyme that catalyzes the sulfate conjugation of primary and secondary alcohols including many hormones, neurotransmitters, drugs, and xenobiotic compounds.- Family members :...
to inactive metabolites. The drug is excreted by feces (~88%) and urine (~5%) with a terminal half life of 12 ± 5 hours.
Clinical studies
A phase III trial in subjects previously treated with docetaxel started in 2008. A placebo-controlled randomised phase III clinical trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009. Encouraging results to be presented in Oct 2010.In September 2010, an independent panel found that the interim results of the phase III clinical trial in previously treated docetaxel patients were so successful that it would have been unethical to keep half the trial participants on placebo, and all patients began receiving the drug. Overall survival was increased by 3.9 months according to this trial. It was approved by the FDA in April 2011 .
The first clinical studies were run by Cancer Research UK's Drug Development Office at the Royal Marsden Hospital, London, and reported in 2004 . A more recent study at the Royal Marsden Hospital, London, in patients who had not received chemotherapy reported in 2007 that abiraterone acetate induced decline in prostate specific antigen
Prostate specific antigen
Prostate-specific antigen also known as gamma-seminoprotein or kallikrein-3 is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family that are secreted by the epithelial cells of the prostate gland...
(PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, normalisation of lactate dehydrogenase. However others cautioned in 2008 that it was too early to know whether abiraterone treatment will have long term benefit.
Results of two phase II trials indicate that abiraterone may reduce prostate specific antigen
Prostate specific antigen
Prostate-specific antigen also known as gamma-seminoprotein or kallikrein-3 is a glycoprotein that in humans is encoded by the KLK3 gene. KLK3 is a member of the kallikrein-related peptidase family that are secreted by the epithelial cells of the prostate gland...
(PSA) levels, as well as shrink tumors. Many of the 21 men in the Phase II trial reported significant improvements in their quality of life and several were able to stop taking morphine, used to control the pain caused after the cancer spread into their bones. On average, progression-free survival (PFS) was prolonged by 161 days in patients which had been treated with chemotherapy, and by 236 days in chemotherapy naive patients. Phase II clinical trials of abiraterone's effectiveness in patients who have not yet received treatment with chemotherapy (33 patients) found a median time to PSA progression of 48 weeks. Another phase II trial in patients who had failed prior treatment with docetaxel (47 patients) showed a median time to PSA progression of 24 weeks.
A phase I/II clinical trial evaluating abiraterone acetate in advanced breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
patients is also underway, run by Cancer Research UK's Drug Development Office.
See also
- MDV3100MDV3100MDV3100 is an experimental androgen receptor antagonist drug developed by the pharmaceutical company Medivation for the treatment of castration-resistant prostate cancer currently in Phase 3 clinical trials. Results so far have been encouraging; Medivation has reported up to an 89% decrease in...
, an oral anti-androgen currently being tested in a phase III clinical trial for use in castration-resistant prostate cancer (CRPC) - OrteronelOrteronelOrteronel is an experimental drug for the treatment of cancer under development by Millennium Pharmaceuticals. It is currently in Phase III clinical trials for metastatic, hormone-refractory prostate cancer....
, a CYP17 inhibitor in phase III clinical trials for CRPC
External links
- Information about abiraterone for UK patients – Cancer Research UKCancer Research UKCancer Research UK is a cancer research and awareness charity in the United Kingdom, formed on 4 February 2002 by the merger of The Cancer Research Campaign and the Imperial Cancer Research Fund. Its aim is to reduce the number of deaths from cancer. As the world's largest independent cancer...
's CancerHelp UK website