Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 2060  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  Article in PDF (589 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  Abstract
 :: Introduction
 ::  What is Castrati...
 :: Abiraterone Acetate
 ::  Research done in...
 ::  References
 ::  Article Figures
 ::  Article Tables

 Article Access Statistics
    Viewed8397    
    Printed182    
    Emailed6    
    PDF Downloaded17    
    Comments [Add]    
    Cited by others 2    

Recommend this journal


 


 
  Table of Contents     
DRUG REVIEW
Year : 2012  |  Volume : 58  |  Issue : 3  |  Page : 203-206

Abiraterone acetate: A novel drug for castration-resistant prostate carcinoma


Department of Pharmacology, Dr. HSJIDS, Panjab University, Sector 25, Chandigarh, Punjab, India

Date of Submission12-Dec-2011
Date of Decision18-Feb-2012
Date of Acceptance11-Mar-2012
Date of Web Publication26-Sep-2012

Correspondence Address:
R Nandha
Department of Pharmacology, Dr. HSJIDS, Panjab University, Sector 25, Chandigarh, Punjab
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.101400

Rights and Permissions


 :: Abstract 

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

How to cite this URL:
Nandha R. Abiraterone acetate: A novel drug for castration-resistant prostate carcinoma. J Postgrad Med [serial online] 2012 [cited 2019 Nov 14];58:203-6. Available from: http://www.jpgmonline.com/text.asp?2012/58/3/203/101400



 :: Introduction Top


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 Top


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 Top


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]
Figure 1: Sites of action of Abiraterone acetate

Click here to view


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 Top


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.
Table 1: Clinical trials of Abiraterone acetate in CRPC patients

Click here to view


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.

 
 :: References Top

1.Kohli M, Tindall DJ. New Developments in the Medical Management of Prostate Cancer. Mayo Clin Proc 2010;85:77-86.  Back to cited text no. 1
[PUBMED]    
2.Nabhan C, Parsons B, Touloukian EZ, Stadler WM. Novel approaches and future directions in castration-resistant prostate cancer. Ann Oncol 2011;22:1948-57.  Back to cited text no. 2
[PUBMED]    
3.Moy B, Lee RJ, Smith M. Natural Products in Cancer Chemotherapy: Hormones and Related agents. In: Brunton L, editor. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill publishers; 2011. p. 1755-69.  Back to cited text no. 3
    
4.Sharifi N, Gulley JL, Dahul WL. An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer 2010;17:305-15.  Back to cited text no. 4
    
5.Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:4448-56.  Back to cited text no. 5
[PUBMED]    
6.Saylor PJ, Smith MR. Adverse effects of androgen deprivation therapy: Defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw 2010;8:211-23.  Back to cited text no. 6
[PUBMED]    
7.Dawson NA, Ryan CJ. Abiraterone and newer antiandrogen compounds for castrate resistant metastatic prostate cancer. Br J Cancer 2009;100:671-5.  Back to cited text no. 7
    
8.Tolcher AW, Cooper J. Castration-resistant prostate cancer: Hormone therapy redux. J Clin Oncol 2010;28:1447-9.  Back to cited text no. 8
[PUBMED]    
9.Yap TA, Zivi A, Omlin A, de Bono JS. The changing therapeutic landscape of castration-resistant prostate cancer. Nat Rev Clin Oncol 2011;8:597-610.  Back to cited text no. 9
[PUBMED]    
10.Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resisitant prostate cancer. J Clin Oncol 2010;28:1496-501.  Back to cited text no. 10
[PUBMED]    
11.Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TA, et al. Increased Expression Of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer. Cancer Res 2006;66:2815-25.  Back to cited text no. 11
    
12.Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol 2004;164:217-27.  Back to cited text no. 12
[PUBMED]    
13.Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, et al. The Androgen Axis in Recurrent Prostate Cancer. Clin Cancer Res 2004;10:440-8.  Back to cited text no. 13
[PUBMED]    
14.Montgomery RB, Mostaghel EA, Vessela R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism in Castration -Resistant Tumor Growth. Cancer Res 2008;68:4447-54.  Back to cited text no. 14
    
15.Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: Established and novel approaches in prostate cancer. Curr Opin Pharmacol 2008;8:449-57.  Back to cited text no. 15
[PUBMED]    
16.Mostaghel EA, Marck B, Plymate S, Vessella RL, Balk SP, Matsumoto AM, et al. Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants. Clin Cancer Res 2011;17:5913-25.  Back to cited text no. 16
    
17.O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, et al. Hormonal impact of the 17alpha-hydroxylase/C (17, 20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 2004;90:2317-25.  Back to cited text no. 17
    
18.Agarwal N, Hutson TE, Vogelzang NJ, Sonpavde G. Abiraterone acetate: A promising drug for the treatment of castration-resistant prostate cancer. Future Oncol 2010;6:665-79.  Back to cited text no. 18
[PUBMED]    
19.Ratain MK. Flushing Oral Oncology Drugs Down the Toilet. J Clin Oncol 2011;29:3958-9.  Back to cited text no. 19
    
20.Jain RK, Brar SS, Lesko LJ. Food and oral antineoplastics: More than meets the eye. Clin Cancer Res 2010;16:4305-7.  Back to cited text no. 20
    
21.Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008;26:4563-71.  Back to cited text no. 21
[PUBMED]    
22.Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol 2010;28:1481-8.  Back to cited text no. 22
[PUBMED]    
23.Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009;27:3742-8  Back to cited text no. 23
    
24.Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, et al. Significant and sustained antitumour activity in post-docetaxel, castration-resisitant prostaste cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 2010;28:1489-95.  Back to cited text no. 24
[PUBMED]    
25.de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med 2011;364:1995-2005.  Back to cited text no. 25
[PUBMED]    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]

This article has been cited by
1 Abiraterone for Treatment of Metastatic Castration-resistant Prostate Cancer: a Systematic Review and Meta-analysis
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]
2 Abiraterone for treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis
Zhou, Z.-R., Liu, S.-X., Zhang, T.-S., Xia, J., Li, B.
Asian Pacific Journal of Cancer. 2014; 15(3): 1313-1320
[Pubmed]



 

Top
Print this article  Email this article
 
Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow