Bicalutamide and the other nonsteroidal antiandrogens (NSAAs), since their introduction, have largely replaced cyproterone acetate (CPA), an older drug and steroidal antiandrogen (SAA), in the treatment of prostate cancer.[1][2][3][4] Bicalutamide was the third NSAA to be marketed, with flutamide and nilutamide preceding, and followed by enzalutamide.[5][6] Relative to the earlier antiandrogens, bicalutamide has substantially reduced toxicity, and in contrast to them, is said to have an excellent and favorable safety profile.[4][7][8][9] For these reasons, as well as superior potency, tolerability, and pharmacokinetics, bicalutamide is preferred and has largely replaced flutamide and nilutamide in clinical practice.[10][11][12] In accordance, bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer.[13][14][15] Between January 2007 and December 2009, it accounted in the U.S. for about 87.2% of NSAA prescriptions.[16] Prior to the 2012 approval of enzalutamide, a newer and improved NSAA with greater potency and efficacy,[7] bicalutamide was regarded as the standard-of-care antiandrogen in the treatment of the prostate cancer.[6][7][17]
Flutamide and nilutamide are first-generation NSAAs, similarly to bicalutamide, and all three drugs possess the same core mechanism of action of being selective AR antagonists.[22] However, bicalutamide is the most potent of the three, with the highest affinity for the AR[23][24] and the longest elimination half-life,[10] and is the safest, least toxic, and best-tolerated.[25] For these reasons, bicalutamide has largely replaced flutamide and nilutamide in clinical use,[26] and is by far the most widely used first-generation NSAA.[16]
Effectiveness
In terms of binding to the AR, the active (R)-enantiomer of bicalutamide has 4-fold greater affinity relative to that of hydroxyflutamide, the active metabolite of flutamide (a prodrug),[27][28] and 5-fold higher affinity relative to that of nilutamide.[21] In addition, bicalutamide possesses the longest elimination half-life of the three drugs,[10] with half-lives of 6–10 days for bicalutamide,[29][30] 5–6 hours for flutamide[4][10] and 8–9 hours for hydroxyflutamide,[4][31][32] and 23–87 hours (mean 56 hours) for nilutamide.[30] Due to the relatively short half-lives of flutamide and hydroxyflutamide, flutamide must be taken three times daily at 8-hour intervals, whereas bicalutamide and nilutamide may be taken once daily.[33] For this reason, dosing of bicalutamide (and nilutamide) is more convenient than with flutamide.[34] The greater AR affinity and longer elimination half-life of bicalutamide allow it to be used at relatively low dosages in comparison to flutamide (750–1500 mg/day) and nilutamide (150–300 mg/day) in the treatment of prostate cancer.[30][35][36]
While it has not been directly compared to nilutamide,[37] the effectiveness of bicalutamide has been found to be at least equivalent to that of flutamide in the treatment of prostate cancer in a direct head-to-head comparison.[38][39] Moreover, indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen (PSA) and testosterone, respectively, were observed.[38][39]
The core side effects of NSAAs such as gynecomastia, sexual dysfunction, and hot flashes occur at similar rates with the different drugs.[48][49] Conversely, bicalutamide is associated with a significantly lower rate of diarrhea compared to flutamide.[37][50] In fact, the incidence of diarrhea did not differ between the bicalutamide and placebo groups (6.3% vs. 6.4%, respectively) in the Early Prostate Cancer (EPC) clinical trial programme,[51] whereas diarrhea occurs in up to 20% of patients treated with flutamide.[37][30] The rate of nausea and vomiting appears to be lower with bicalutamide and flutamide than with nilutamide (approximately 30% incidence of nausea with nilutamide, usually rated as mild-to-moderate).[52][53] In addition, bicalutamide (and flutamide) is not associated with alcoholintolerance, visual disturbances, or a high rate of interstitial pneumonitis.[37][50] In terms of toxicity and rare reactions, as described above, bicalutamide appears to have the lowest relative risks of hepatotoxicity and interstitial pneumonitis, with respective incidences far below those of flutamide and nilutamide.[30][54][55][56] In contrast to flutamide and nilutamide, no unique or specific complications have been linked to bicalutamide.[18]
Enzalutamide, along with the in-development apalutamide and darolutamide, are newer, second-generation NSAAs.[60] Similarly to bicalutamide and the other first-generation NSAAs, they possess the same core mechanism of action of selective AR antagonism but are thought to bind to the androgen receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity. Theoretically such increased affinity may make them more efficacious.[60] This is because cancer cells use different mechanisms to adapt and this increased affinity for the receptor make it more likely to bind to mutated receptors, to increased production of the receptors, and perhaps other mechanisms of resistance.[60]
Effectiveness
In comparison to bicalutamide, enzalutamide has 5- to 8-fold higher affinity for the AR,[61][62][63][64] possesses mechanistic differences resulting in improved AR deactivation,[61][65] shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[61][66] and has an even longer elimination half-life (8–9 days versus ~6 days for bicalutamide).[67] In accordance, clinical findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide.[68][47] Moreover, the medication has demonstrated greater clinical effectiveness in the treatment of prostate cancer in direct head-to-head comparisons with bicalutamide.[69]
Tolerability and safety
In terms of tolerability, enzalutamide and bicalutamide appear comparable in most regards, with a similar moderate negative effect on sexual function and activity for instance.[68] However, enzalutamide has a risk of seizures and other central side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have.[67][70] On the other hand, unlike with all of the earlier NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[71][72] In addition to differences in adverse effects, enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 and poses a high risk of major drug interactions (CYP3A4 alone being involved in the metabolism of approximately 50 to 60% of clinically important drugs),[73][74] whereas drug interactions are few and minimal with bicalutamide.[75][9]
Steroidal antiandrogens
SAAs include cyproterone acetate (CPA), megestrol acetate, chlormadinone acetate, and spironolactone.[76][77] These drugs are steroids, and similarly to NSAAs, act as competitive antagonists of the AR, reducing androgenic activity in the body.[78]: 79 In contrast to NSAAs however, they are non-selective, also binding to other steroid hormone receptors, and exhibit a variety of other activities including progestogenic, antigonadotropic, glucocorticoid, and/or antimineralocorticoid.[76][77] In addition, they are not silent antagonists of the AR, but are rather weak partial agonists with the capacity for both antiandrogenic and androgenic actions.[78][79][80] Of the SAAs, CPA is the only one that has been widely used in the treatment of prostate cancer.[28]: 488 As antiandrogens, the SAAs have largely been replaced by the NSAAs and are now rarely used in the treatment of prostate cancer, due to the superior selectivity, efficacy, and tolerability profiles of NSAAs.[1][2][3][4] However, some of them, namely CPA and spironolactone, are still commonly used in the management of certain androgen-dependent conditions (e.g., acne and hirsutism in women) and as the antiandrogen component of feminizing hormone therapy for transgender women.[35]: 1195–6 [81]
Effectiveness
In a large-scale clinical trial that compared 750 mg/day flutamide and 250 mg/day CPA monotherapies in the treatment of men with prostate cancer, the two drugs were found to have equivalent effectiveness on all endpoints.[82] In addition, contrarily to the case of men, flutamide has been found in various clinical studies to be more effective than CPA (and particularly spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[83][84][85] This difference in effectiveness in men and women may be related to the fact that NSAAs like flutamide significantly increase androgen levels in men,[35] which counteracts their antiandrogenic potency,[86] but do not increase androgen levels in women.[87] (In contrast to NSAAs, CPA, due to its progestogenic and hence antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)[35]
Bicalutamide has been found to be at least as effective as or more effective than flutamide in the treatment of prostate cancer,[38][39] and is considered to be the most potent and efficacious antiandrogen of the three first-generation NSAAs.[82] As such, although bicalutamide has not been compared head-to-head to CPA or spironolactone in the treatment of androgen-dependent conditions, flutamide has been found to be either equivalent or more effective than them in clinical studies, and the same would consequently be expected of bicalutamide. Accordingly, a study comparing the efficacy of 50 mg/day bicalutamide versus 300 mg/day CPA in preventing the PSA flare at the start of GnRH agonist therapy in men with prostate cancer found that the two regimens were equivalently effective.[88] There was evidence of a slight advantage in terms of speed of onset and magnitude for the CPA group, but the differences were small and did not reach statistical significance.[88] The differences may have been related to the antigonadotropic activity of CPA (which would directly counteract the GnRH agonist-induced increase in gonadal androgen production) and/or the fact that bicalutamide requires 4 to 12 weeks of administration to reach steady-state (maximal) levels.[75][88]
All medically used SAAs are weak partial agonists of the AR rather than silent antagonists, and for this reason, possess inherent androgenicity in addition to their predominantly antiandrogenic actions.[78][79][80] In accordance, although CPA produces feminization of and ambiguous genitalia in male fetuses when administered to pregnant animals,[89] it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.[79] Additionally, all SAAs, including CPA and spironolactone, have been found to stimulate and significantly accelerate the growth of androgen-sensitive tumors in the absence of androgens, whereas NSAAs like flutamide have no effect and can in fact antagonize the stimulation caused by SAAs.[79][80][90] Accordingly, unlike NSAAs, the addition of CPA to castration has never been found in any controlled study to prolong survival in prostate cancer to a greater extent than castration alone.[79] In fact, a meta-analysis found that the addition of CPA to castration actually reduces the long-term effectiveness of ADT and causes an increase in mortality (mainly due to cardiovascular complications induced by CPA).[91] Also, there are two case reports of spironolactone actually accelerating progression of metastatic prostate cancer in castrated men treated with it for heart failure, and for this reason, spironolactone has been regarded as contraindicated in patients with prostate cancer.[92][93] Because of their intrinsic capacity to activate the AR, SAAs are incapable of maximally depriving the body of androgen signaling, and will always maintain at least some degree of AR activation.[80][90]
Due to its progestogenic (and by extension antigonadotropic) activity, CPA is able to suppress circulating testosterone levels by 70 to 80% in men at high dosages.[25][94] In contrast, NSAAs increase testosterone levels by up to 2-fold via blockade of the AR, a difference that is due to their lack of concomitant antigonadotropic action.[95] However, in spite of the combined AR antagonism and marked suppression of androgen levels by CPA (and hence a sort of CAB profile of antiandrogen action), monotherapy with an NSAA, CPA, or a GnRH analogue/castration all have about the same effectiveness in the treatment of prostate cancer,[94][19] whereas CAB in the form of the addition of bicalutamide (but not of CPA) to castration has slightly but significantly greater comparative effectiveness in slowing the progression of prostate cancer and extending life.[79][19] These differences may be related to the inherent androgenicity of CPA, which likely serves to limit its clinical efficacy as an antiandrogen in prostate cancer.[78][79][80][96]
Tolerability and safety
Due to the different hormonal activities of NSAAs like bicalutamide and SAAs like CPA, they possess different profiles of adverse effects.[18] CPA is regarded as having an unfavorable side effect profile,[37] and the tolerability of bicalutamide is considered to be superior.[3][55] Due to its strong antigonadotropic effects and suppression of androgen and estrogen levels, CPA is associated with marked sexual dysfunction (including loss of libido and impotence) similar to that seen with castration,[37][18][97] and osteoporosis,[98] whereas such side effects occur minimally with NSAAs like bicalutamide.[75][18] In addition, CPA has been associated with coagulation changes[91] and thrombosis,[79][97]fluid retention,[97] cardiovascular side effects (e.g., ischemic cardiomyopathy),[99][100] and adverse effects on serumlipid profiles,[37][79][18] with severe cardiovascular complications[18] occurring in approximately 10% of men with prostate cancer.[52] In contrast, bicalutamide and other NSAAs are not associated with these adverse effects.[101] Moreover, high doses of CPA are associated with hepatotoxicity,[37][102] whereas the risk of hepatotoxicity appears to be smaller with bicalutamide.[103][104] CPA has also been associated with psychological side effects such as depression, fatigue, and irritability.[105][106][107][108]
It has been said that the only advantage of CPA over castration is its relatively low incidence of hot flashes, a benefit that is mediated by its progestogenic activity.[97] Due to increased estrogen levels, bicalutamide and other NSAAs are similarly associated with low rates of hot flashes (9.2% for bicalutamide vs. 5.4% for placebo in the EPC trial).[75] One advantage of CPA over NSAAs is that, because it suppresses estrogen levels rather than increases them, it is associated with only a low rate of what is generally only slight gynecomastia (4–20%),[97][109][48] whereas NSAAs are associated with rates of gynecomastia of up to 80%.[110] Although NSAA monotherapy has many tolerability advantages in comparison to CPA, a few of these advantages, such as preservation of sexual function and interest and BMD (i.e., no increased incidence of osteoporosis) and low rates of hot flashes, are lost when NSAAs are combined with castration.[111] However, the risk and severity of gynecomastia with NSAAs are also greatly diminished in this context.[48][46]
Castration consists of either medical castration with a GnRH analogue or surgical castration via orchiectomy.[31] GnRH analogues include GnRH agonists like leuprorelin or goserelin and GnRH antagonists like cetrorelix.[31] They are powerful antigonadotropins and work by abolishing the GnRH-induced secretion of gonadotropins, in turn ceasing gonadal production of sex hormones.[31] Medical and surgical castration achieve essentially the same effect, decreasing circulating testosterone levels by approximately 95%.[31][119]
Effectiveness
Bicalutamide monotherapy has been reported to be roughly equivalent in effectiveness compared to GnRH analogues and castration in the treatment of prostate cancer.[4][78][82] A meta-analysis concluded that there is a slight effectiveness advantage for GnRH analogues/castration, but the differences trended towards but did not reach statistical significance in that study.[4][78][82][120] In mPC, the median survival time was found to be only 6 weeks shorter with bicalutamide monotherapy in comparison to GnRH analogue monotherapy.[121] However, a 2015 Cochrane review reported lower overall survival times (HRTooltip hazard ratio = 1.24), greater clinical progression (RRTooltip risk ratio = 1.14–1.26), and treatment failure (RR = 1.14–1.27) with NSAA monotherapy compared to monotherapy with a GnRH agonist or surgical castration.[122]
Tolerability and safety
Monotherapy with NSAAs including bicalutamide, flutamide, nilutamide, and enzalutamide shows a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, CAB (NSAA and GnRH analogue combination), CPA, or surgical castration in prostate cancer.[51][49][123][124] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for CAB and 69% reported complete loss of erectile function relative to 93% for CAB.[51] Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care.[125] One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo.[126] It has been proposed that due to the lower relative effect of NSAAs on sexual interest and activity, with two-thirds of advanced mPC patients treated with them retaining sexual interest, these drugs may result in improved quality of life and thus be preferable for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.[49] Also, bicalutamide differs from GnRH analogues (which decrease BMD and significantly increase the risk of bone fractures)[127] in that it has well-documented benefits on BMD, effects that are likely due to increased levels of estrogen.[120][128]
A 2015 Cochrane review found that NSAA monotherapy for prostate cancer had a greater risk of treatment discontinuation due to adverse effects than monotherapy with a GnRH agonist or surgical castration (RR = 1.82).[122] This included a greatly increased risk of breast pain (RR = 22.97) and gynecomastia (RR = 8.43).[122] The risk of other adverse effects, such as hot flashes (RR = 0.23), was decreased with NSAA monotherapy.[122] The quality of the evidence was deemed moderate.[122]
^ abcPayen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont MA, McGlinchey MJ, Müller-Bunz H, Jaouen G (2011). "Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide". Journal of Organometallic Chemistry. 696 (5): 1049–1056. doi:10.1016/j.jorganchem.2010.10.051. Cyproterone acetate was one of the first steroidal antiandrogen clinically used but its side-effects, especially the interaction with the progestin and glucocorticoid receptor, made this drug less popular than the nonsteroidal antiandrogens such as nilutamide [3,4], flutamide [5–7] and bicalutamide [8].
^ abcdefgChabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–680. ISBN978-1-60547-431-1. From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
^ abcVogelzang NJ (September 2012). "Enzalutamide—a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine. 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID23013078. S2CID32314622. The first nonsteroidal antiandrogen agents — flutamide, nilutamide, and bicalutamide2 — were shown to be less effective than castration in cases of metastatic castration-resistant prostate cancer, but bicalutamide is still widely used as a moderately effective secondary hormone therapy because of an excellent safety profile.
^Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN978-3-319-13278-5. Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma.
^ abKolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9, discussion 80–4. doi:10.1016/s0090-4295(96)80012-4. PMID8560681. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.
^Campbell T (22 January 2014). "Slowing Sales for Johnson & Johnson's Zytiga May Be Good News for Medivation". The Motley Fool. Archived from the original on 26 August 2016. Retrieved 20 July 2016. [...] the most commonly prescribed treatment for metastatic castration resistant prostate cancer: bicalutamide. That was sold as AstraZeneca's billion-dollar-a-year drug Casodex before losing patent protection in 2008. AstraZeneca still generates a few hundred million dollars in sales from Casodex, [...]
^ abcdefgAronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–152. ISBN978-0-08-093292-7. In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide.
^ abcWirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13, discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID17007995.
^ abcdeKolvenbag, Geert J. C. M.; Furr, Barrington J. A. (2009). "Nonsteroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN978-1-60761-471-5. A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).
^Boccardo F (August 2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?". Critical Reviews in Oncology/Hematology. 35 (2): 121–32. doi:10.1016/S1040-8428(00)00051-2. PMID10936469.
^Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7 –R9. doi:10.1677/joe.0.113R007. PMID3625091.
^Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D (January 1994). "Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 48 (1): 111–119. doi:10.1016/0960-0760(94)90257-7. PMID8136296. S2CID31404295.
^Winneker RC, Wagner MM, Batzold FH (December 1989). "Studies on the mechanism of action of Win 49596: a steroidal androgen receptor antagonist". Journal of Steroid Biochemistry. 33 (6): 1133–1138. doi:10.1016/0022-4731(89)90420-2. PMID2615358.
^ abLuo S, Martel C, Leblanc G, Candas B, Singh SM, Labrie C, Simard J, Bélanger A, Labrie F (1996). "Relative potencies of Flutamide and Casodex: preclinical studies". Endocrine Related Cancer. 3 (3): 229–241. doi:10.1677/erc.0.0030229. ISSN1351-0088.
^Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". Journal of Steroid Biochemistry. 33 (2): 251–255. doi:10.1016/0022-4731(89)90301-4. PMID2788775.
^Kemppainen JA, Wilson EM (July 1996). "Agonist and antagonist activities of hydroxyflutamide and Casodex relate to androgen receptor stabilization". Urology. 48 (1): 157–163. doi:10.1016/S0090-4295(96)00117-3. PMID8693644.
^ abcBautista-Vidal C, Barnoiu O, García-Galisteo E, Gómez-Lechuga P, Baena-González V (2014). "Treatment of gynecomastia in patients with prostate cancer and androgen deprivation". Actas Urologicas Españolas. 38 (1): 34–40. doi:10.1016/j.acuro.2013.02.013. PMID23850393. The frequency of occurrence of gynecomastia with the use of antiandrogens with gonadotrophin-releasing hormone agonists is about 15%, but the frequency of gynecomastia with antiandrogens in monotherapy is rather similar; thus, we found gynecomastia rates of around 43–76% with flutamide, 79% with nilutamide, and between 47 and 85% with bicalutamide.
^ abRicci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID25270521. S2CID207488100.
^ abcDicker AP (2003). "The safety and tolerability of low-dose irradiation for the management of gynaecomastia caused by antiandrogen monotherapy". The Lancet Oncology. 4 (1): 30–6. doi:10.1016/s1470-2045(03)00958-6. PMID12517537.
^ abBlackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". European Urology. 29 Suppl 2 (2): 96–104. doi:10.1159/000473847. PMID8717470. Casodex is associated with significantly less gastrointestinal effects (diarrhoea) than the nonsteroidal antiandrogen flutamide (Eulexin, Schering-Plough International). Casodex is not associated with alcohol intolerance, pneumonitis and ocular defects which have been seen with the antiandrogen nilutamide (Anandron, Roussel).
^ abcFradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy. 4 (1): 37–48. doi:10.1586/14737140.4.1.37. PMID14748655. S2CID34153031. In contrast, the incidence of diarrhea was comparable between the bicalutamide and placebo groups (6.3 vs. 6.4%, respectively) in the EPC program [71].
^Harris MG, Coleman SG, Faulds D, Chrisp P (1993). "Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs & Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. PMID8453188.
^Bennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID12353966. An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.
^"Casodex Product Monograph"(PDF). Retrieved 24 September 2018. Table 1 Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality [...] Increased Liver Enzyme Test: [...] [Number of Patients (%)] [...] CASODEX Plus LHRH Analog (n=401): 30 (7 [7.5%) [...] Flutamide Plus LHRH Analog (n=407): 46 (11 [11.3%]).
^"NU-Bicalutamide Product Monograph"(PDF). Retrieved 24 September 2018. Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure and interstitial lung disease (see WARNINGS AND PRECAUTIONS) have been observed in post-marketed data and fatal outcomes have been reported for both. [...] The most common adverse events leading to withdrawal of study medication were abnormal liver function tests (1.5%) [...] Table 1 Incidence Of Adverse Events (≥ 5% In Either Treatment Group) Regardless Of Causality [...] Increased Liver Enzyme Testb [Number of Patients (%)] [...] CASODEX Plus LHRH Analogue (n=401): 30 (7 [7.5%]) [...] Flutamide Plus LHRH Analogue (n=407): 46 (11 [11.3%]) [...] During the first few months of use, you may be monitored by your physician for signs of changes in your liver function. In approximately 2.0% of patients, such changes may lead to withdrawal of therapy.
^Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. doi:10.1159/000473847. PMID8717470. Casodex has been administered to over 3,900 subjects and patients and, in general, has been well tolerated. [...] Elevations of liver transaminases have been seen with Casodex, but these are usually transient, resolving either on continued therapy or on temporary cessation of therapy. In a randomised comparison with flutamide, elevations of transaminases were both less frequent and less severe than with flutamide. No cases of fulminant hepatic failure or death due to hepatic failure have been seen with Casodex in any of the clinical trials.
^Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID20878947. S2CID24620044.
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^ abMüller E (18 September 2003). Peptides and Non Peptides of Oncologic and Neuroendocrine Relevance: From Basic to Clinical Research. Springer Science & Business Media. pp. 171–. ISBN978-88-470-0295-1. Archived from the original on 8 September 2017. [CPA] induces relevant effects on the coagulative system. A recent meta-analysis relating to total androgenic blockade has shown that cyproterone acetate when combined with castration reduces the long-term efficacy of androgen-suppressive treatments. In fact, it causes an increase in treatment-related mortality, mainly due to cardiovascular complications (No authors, 2000).
^Jameson JL, de Kretser DM, Marshall JC, De Groot LJ (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN978-0-323-22152-8. Archived from the original on 25 July 2014. Nonsteroidal antiandrogens (e.g., flutamide and nilutamide) are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol.119 The latter is desirable in this context, as it has feminizing effects.
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