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| DRUG REVIEW |
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| Year : 2012 | Volume
: 58
| Issue : 3 | Page : 203-206 |
Abiraterone acetate: A novel drug for castration-resistant prostate carcinoma
R Nandha
Department of Pharmacology, Dr. HSJIDS, Panjab University, Sector 25, Chandigarh, Punjab, India
| Date of Submission | 12-Dec-2011 |
| Date of Decision | 18-Feb-2012 |
| Date of Acceptance | 11-Mar-2012 |
| Date of Web Publication | 26-Sep-2012 |
Correspondence Address:
R Nandha
Department of Pharmacology, Dr. HSJIDS, Panjab University, Sector 25, Chandigarh, Punjab
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.101400
Androgen-deprivation therapy is the mainstay of treatment for the management of advanced prostate carcinoma till transition to castration-resistant prostate carcinoma (CRPC). Recently, adrenal and intratumoral synthesis of androgens has been found to be the major cause for CRPC. Abiraterone acetate is an orally active, potent and selective inhibitor of 17 a hydroxylase and c 17, 20 lyase, which acts by decreasing the de novo production of androgens with no rise in steroids downstream. Multiple randomized trials have shown significant improvement of >50% decline in prostate-specific antigen (PSA) and time to PSA progression (TTPP) with abiraterone acetate 1000 mg per day in chemotherapy/ketoconazole treated and naive CRPC patients producing reversible and manageable adverse effects due to mineralocorticoid excess. This article reviews the available evidence on efficacy and safety of this drug in CRPC. Searches of Pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made for terms like CRPC and abiraterone.
Keywords: 17 α hydroxylase and c17, 20 lyase inhibitors, abiraterone acetate, castration-resistant prostate carcinoma
How to cite this article:
Nandha R. Abiraterone acetate: A novel drug for castration-resistant prostate carcinoma. J Postgrad Med 2012;58:203-6 |
| :: Introduction | |  |
Prostate cancer is the most common cancer in men in the United States and the third most common cause of cancer mortality, with an estimated 27,360 deaths out of 1,98,280 diagnosed cases in 2009. [1],[2] Increased awareness of disease and developed methods for rapid and early detection of cancer allow early treatment when the tumour is still sensitive. Elucidation of the structural and functional correlation of androgen receptors in prostate biology gave direction for the development of drugs for the management of prostate carcinoma. [1] Localised prostate cancer is frequently curable with surgery or radiation therapy, but, when disease progresses with distant metastasis, hormonal therapy is the primary treatment. [3] Standard treatment of men with prostate carcinoma includes the use of androgen deprivation therapy (ADT), irrespective of whether it is medical [use of antiandrogens-gonadotropin releasing hormone (GnRH) agonists: Leuprolide, Goserelin and GnRH antagonists: Degarelix] or bilateral surgical orchiectomy. Over one-third of the men have been demonstrated to be treated with ADT of 2 million who are currently diagnosed with prostate cancer in the United States. [4],[5],[6]
| :: What is Castration-resistant Prostate Carcinoma | | |
Despite initial response to ADT in 80% of the patients, all advanced prostate cancers become refractory to hormonal therapy. At such stage, when cancer progresses eventually, despite ADT, it is labelled as "Castration-Resistant Prostate Carcinoma" (CRPC). [2],[7] CRPC is the progressive form of prostate cancer with rising prostate-specific antigen (PSA) levels, and represents a transition to lethal phenotype of the disease to which majority of the patients succumb where less than 20% of men survive beyond 3 years. Its substantial contribution to morbidity and mortality necessitates a keen attention toward the management of this deadly disease.
As CRPC is not curable, the primary aim is palliative management to increase lifespan and to relieve symptoms. Management of CRPC includes chemotherapy, second-line hormonal therapy, radiotherapy and other supportive therapies. Docetaxel is the first-line approach in CRPC patients. However, in spite of improved survival and reduction in tumour burden, inability to produce response in 50% of the patients and development of resistance limit its use. Hematological and non-hematological toxicities also make Docetaxel less satisfactory and, as patients of CRPC are old aged or with co-morbidities, its use becomes more unacceptable. [7],[8],[9]
Multiple mechanisms are proposed in the pathogenesis of CRPC, which include wandrogen receptor (AR) overexpression through AR gene amplification, splice variant mutations in AR structure and function, increased AR activation by nuclear co-activators and some AR-independent mechanisms. [2] Overexpression of AR is the most common mechanism underlying CRPC. [10],[11] Androgens originating from other sources, including the adrenal gland and, intriguingly, the prostate cancer itself, may continue to act as a ligand and result in AR signalling. In 2004, increase in adrenal and intratumoral androgen synthesis has been reported to be an additional mechanism due to a five-fold induction of several enzymes involved in steroid hormone production in CRPC. [12],[13] Thus, CRPC has been tagged as paracrine/autocrine instead of endocrine androgen-dependent carcinoma. [14] Various other studies thereafter also demonstrated that despite medical/surgical castration, androgen is being synthesised both by adrenals and by intratumoral tissues as key enzymes 17 a hydroxylase /c17-20 lyase are also expressed in them. [10],[14] De novo extratesticular androgen synthesis is sufficient enough to propel growth of prostate carcinoma because of continuous AR signalling, suggesting a new target for drugs blocking the synthesis or the receptors of not only adrenal androgens but also intratumoral androgens that were not being inhibited by conventional hormonal therapies. [13],[14],[15] This gave a new direction for inventing new secondary hormonal therapies for those patients who develop resistance or contraindication to Docetaxel therapy. Secondary therapies targeting hormones are to further deplete androgens either by blocking synthesis (Ketoconazole, Abiraterone) or ARs (Bicalutamide, Nilutamide, Flutamide, MDV3100). Among the synthesis blockers, Ketoconazole, an antifungal drug, was found to secondarily inhibit adrenal and intratumoral androgen synthesis, which is the key culprit responsible for the progression of CRPC. Ketoconazole is a non-selective inhibitor of the CYP17 enzyme. Being a potent inhibitor of side-chain cleavage enzyme playing a key role in steroidogenesis, it has been demonstrated to cause significant decrease in Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone sulfate (DHEAS) and androstenedione. Thus, a patient on ketoconazole therapy is at continuous risk of adrenal insufficiency, requiring steroid replacement therapy. Another drawback with its use, which has been seen, is incomplete target blockade leading to the development of resistance because of increase in androgen production with disease progression. Adverse effects and drug interactions with statins and antidepressants further limit its use. [7] Therefore, the search for a better option ended up in the development of "Abiraterone" through screening of the chemical derivative of pregnenalone. This article reviews the available evidence on the efficacy and safety of this drug in chemotherapy/Ketoconazole-naive as well as treated patients of CRPC. Searches of Pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made for terms like Abiraterone acetate and CRPC. Relevant journal articles were chosen to provide necessary information.
| :: Abiraterone Acetate | | |
Abiraterone acetate is an orally effective, selective, irreversible and potent inhibitor of 17 a-hydroxylase and c17, 20-lyase, critical enzymes that catalyze two key steroid reactions in the testosterone synthesis pathway [1],[2],[3],[8],[16],[17] [Figure 1]. Abiraterone (17-(3-pyridyl) androsta-5,16-dien-3b-ol), a pregnenolone-derived compound, is a 3-pyridyl steroid that was originally developed by chemists at the Institute of Cancer Research in the United Kingdom. While the 16, 17-double bond in abiraterone is responsible for its irreversible binding to CYP17, the 3-pyridyl substitution results in its potent and selective inhibition of CYP17. Its 3 β-O-acetate form (Abiraterone acetate) has been developed to increase the bioavailability. [18] Several studies have shown that inhibition of key enzymes-17 a hydroxylase /c17-20 lyase causes maximum suppression of testosterone synthesis in both castrated and non-castrated men with CRPC, with significantly better results in castrated males. [8],[17]
Abiraterone irreversibly inhibits the products of CYP17 gene - 17 a hydroxylase and c 17-20 lyase - thus decreasing the production of androgens in adrenal glands and tumour tissue with no rise in steroids downstream of CYP17, indicating durable, irreversible CYP17 inhibition. [7],[15] Abiraterone differs from Ketoconazole in being irreversible, selective and 10-times more potent, having no propensity to produce adrenal insufficiency.
Controversy lies regarding administration of Abiraterone with meals. It has been labelled to be taken fasting despite its better bioavailability when taken with food, given that the explanation for fasting intake is the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications, due to which the drug is preferred to be taken fasting even if bioavailability after fasting is <10%. [19],[20]
| :: Research done in this Area | | |
The effectiveness of Abiraterone acetate has been addressed in multiple randomized clinical trials [Table 1]. A dose of 1000 mg per day was fixed as the standard dose in the phase I clinical trial done by Attard et al., to be further used in phase II trials because of the plateau of endocrine effects at doses greater than 750 mg and less than 1000 mg. [21] The phase I trial done by Ryan et al. showed that Abiraterone acetate at the dose of 1000 mg is a safe and efficacious alternative for both Ketoconazole-naive and -treated patients. [22] Three phase II trials have investigated the use of Abiraterone acetate to treat CRPC. All were small, single-arm, open-label studies, and enrolled 47, 42 and 58 patients each. Trials have been done both in chemo/Ketoconazole-naive as well as pre-treated patients. The phase II trial done by Attard et al. was done on men who were chemotherapy-naοve, while the trials done by Danila et al. and Reid et al. examined men who had been previously treated with docetaxel-based chemotherapy. [10],[23],[24] The phase II trials showed a ≥50% decrease in PSA levels in 36% and 51% of docetaxel-treated patients and 67% of chemotherapy-naive patients following treatment with Abiraterone acetate. A recent phase III trial found that Abiraterone acetate increased survival in docetaxel-treated men with CRPC to 14.8 months, compared with 10.9 months in the placebo group (hazard ratio 0.65, 95% confidence interval 0.54-0.77, P <0.0001). The secondary end points of time to PSA progression, radiographic progression-free survival and PSA response were all significantly improved in patients taking Abiraterone. [25] Adverse effects caused by Abiraterone were because of mineralocorticoid excess, including hypokalemia, hypertension and edema, all of which are easily manageable by either aldosterone antagonist-Eplerenone or use of low-dose steroids. [8] Other adverse effects noticed in patients were hot flushes, anorexia, nausea, abnormal liver function tests, headache, precipitation of migraine and bronchial asthma. Grade 3 and grade 4 adverse effects were rare in various trials. The results of all the trials depicted a favorable response with the use of Abiraterone acetate, with tolerable and easily manageable adverse effects. No information on the cost of abiraterone is currently available. Recently, on April 28 2011. the US-FDA has approved Abiraterone in combination with Prednisolone for the treatment of CRPC in men who have received prior Docetaxel therapy. Another ongoing phase III randomized double-blind, placebo-controlled clinical trial (COU-002) of Abiraterone acetate with Prednisolone in metastatic CRPC patients who have failed prior Docetaxel therapy is near completion in 2012.
To conclude, Abiraterone acetate is an approved drug to be used in combination with Prednisolone in CRPC patients who had prior Docetaxel therapy. It can serve as a new therapy affirming a steady, safe and efficacious response if given along with 10 mg Prednisolone daily, with the need to monitor potassium levels and blood pressure. Longer follow-up studies are warranted in the future to evaluate the late toxic effects of this new drug. Moreover, studies to ascertain the optimal sequencing or combinations of Abiraterone with additional novel hormonal agents that are poised for FDA approval such as MDV3100 can expand the treatment strategies for metastatic CRPC.
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[Figure 1]
[Table 1]
| This article has been cited by | | 1 |
Abiraterone for treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis |
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| Zhou, Z.-R., Liu, S.-X., Zhang, T.-S., Xia, J., Li, B. | | Asian Pacific Journal of Cancer. 2014; 15(3): 1313-1320 | | [Pubmed] | | | 2 |
Abiraterone for Treatment of Metastatic Castration-resistant Prostate Cancer: a Systematic Review and Meta-analysis |
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| Zhi-Rui Zhou,Shi-Xin Liu,Tian-Song Zhang,Jun Xia,Bo Li | | Asian Pacific Journal of Cancer Prevention. 2014; 15(3): 1313 | | [Pubmed] | [DOI] | |
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