Comparison of bicalutamide with other antiandrogens explained

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

Relative to steroidal antiandrogens like cyproterone acetate and spironolactone, bicalutamide has better selectivity in its action, superior efficacy as an antagonist of the androgen receptor, and better tolerability. Bicalutamide also shows a better safety profile than cyproterone acetate. When used as a high-dosage monotherapy, bicalutamide shows slightly inferior effectiveness in the treatment of prostate cancer compared to castration and GnRH analogues but a different and potentially superior tolerability and safety profile. Unlike antigonadotropic antiandrogens like cyproterone acetate and GnRH analogues, bicalutamide does not suppress production of testosterone or estradiol and instead actually increases it, which has an important involvement in the differential side-effect profiles of the medications.

Overview

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 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.[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 for about 87.2% of prescriptions. Prior to the 2012 approval of enzalutamide, a newer and improved with greater potency and efficacy, bicalutamide was regarded as the standard-of-care antiandrogen in the treatment of the prostate cancer.[16]

First-generation

Comparison of first-generation
Property Bicalutamide
Half-life 5–6 hours ~2 days ~7 days
25% 20% 100%
Dosage 250 mg 100 mg 150 mg
Unique side
effects/risks 		• Diarrhea
• Hepatotoxicity
• Photosensitivity 		• Nausea and vomiting
• Visual disturbances
• Alcohol intolerance
• Interstitial pneumonitis 		• None[17]
Sources: [18] [19]

Flutamide and nilutamide are first-generation, similarly to bicalutamide, and all three drugs possess the same core mechanism of action of being selective antagonists.[20] However, bicalutamide is the most potent of the three, with the highest affinity for the [21] [22] and the longest elimination half-life, and is the safest, least toxic, and best-tolerated.[23] For these reasons, bicalutamide has largely replaced flutamide and nilutamide in clinical use,[24] and is by far the most widely used first-generation .

Effectiveness

In terms of binding to the, the active (R)-enantiomer of bicalutamide has 4-fold greater affinity relative to that of hydroxyflutamide, the active metabolite of flutamide (a prodrug),[25] [26] and 5-fold higher affinity relative to that of nilutamide.[27] In addition, bicalutamide possesses the longest elimination half-life of the three drugs, with half-lives of 6–10 days for bicalutamide,[28] [29] 5–6 hours for flutamide and 8–9 hours for hydroxyflutamide,[30] [31] and 23–87 hours (mean 56 hours) for nilutamide. 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.[32] For this reason, dosing of bicalutamide (and nilutamide) is more convenient than with flutamide.[33] The greater 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.[34] [35]

While it has not been directly compared to nilutamide, 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.[36] Moreover, indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen (PSA) and testosterone, respectively, were observed.

Tolerability and safety

Comparative tolerability of
Side effect
Hot flashes
Visual disturbances
Seizures
Key: : Not reported; : ≥ 1%, < 20%;
: ≥ 20%, < 40%; : ≥ 40%. Sources:

The core side effects of such as gynecomastia, sexual dysfunction, and hot flashes occur at similar rates with the different drugs.[37] Conversely, bicalutamide is associated with a significantly lower rate of diarrhea compared to flutamide.[38] [39] 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,[40] whereas diarrhea occurs in up to 20% of patients treated with flutamide. 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).[41] [42] In addition, bicalutamide (and flutamide) is not associated with alcohol intolerance, visual disturbances, or a high rate of interstitial pneumonitis. 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.[43] [44] [45] In contrast to flutamide and nilutamide, no unique or specific complications have been linked to bicalutamide.

Second-generation

Enzalutamide, along with the in-development apalutamide and darolutamide, are newer, second-generation .[46] Similarly to bicalutamide and the other first-generation, they possess the same core mechanism of action of selective 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. 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.

Effectiveness

In comparison to bicalutamide, enzalutamide has 5- to 8-fold higher affinity for the,[47] [48] [49] [50] possesses mechanistic differences resulting in improved deactivation,[51] shows increased (though by no means complete) resistance to mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[52] and has an even longer elimination half-life (8–9 days versus ~6 days for bicalutamide).[53] 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.[54] [55] Moreover, the medication has demonstrated greater clinical effectiveness in the treatment of prostate cancer in direct head-to-head comparisons with bicalutamide.[56]

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. 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.[57] On the other hand, unlike with all of the earlier (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.[58] [59] 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),[60] [61] whereas drug interactions are few and minimal with bicalutamide.[62]

Steroidal antiandrogens

include cyproterone acetate (CPA), megestrol acetate, chlormadinone acetate, and spironolactone.[63] [64] These drugs are steroids, and similarly to, act as competitive antagonists of the, reducing androgenic activity in the body.[65] In contrast to 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. In addition, they are not silent antagonists of the, but are rather weak partial agonists with the capacity for both antiandrogenic and androgenic actions.[66] [67] Of the, is the only one that has been widely used in the treatment of prostate cancer. As antiandrogens, the have largely been replaced by the and are now rarely used in the treatment of prostate cancer, due to the superior selectivity, efficacy, and tolerability profiles of . However, some of them, namely 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.[68]

Effectiveness

In a large-scale clinical trial that compared 750 mg/day flutamide and 250 mg/day monotherapies in the treatment of men with prostate cancer, the two drugs were found to have equivalent effectiveness on all endpoints.[69] In addition, contrarily to the case of men, flutamide has been found in various clinical studies to be more effective than (and particularly spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[70] [71] [72] This difference in effectiveness in men and women may be related to the fact that like flutamide significantly increase androgen levels in men, which counteracts their antiandrogenic potency,[73] but do not increase androgen levels in women.[74] (In contrast to,, due to its progestogenic and hence antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)

Bicalutamide has been found to be at least as effective as or more effective than flutamide in the treatment of prostate cancer,[75] and is considered to be the most potent and efficacious antiandrogen of the three first-generation . As such, although bicalutamide has not been compared head-to-head to 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 in preventing the flare at the start of agonist therapy in men with prostate cancer found that the two regimens were equivalently effective.[76] There was evidence of a slight advantage in terms of speed of onset and magnitude for the group, but the differences were small and did not reach statistical significance. The differences may have been related to the antigonadotropic activity of (which would directly counteract the 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.

All medically used are weak partial agonists of the rather than silent antagonists, and for this reason, possess inherent androgenicity in addition to their predominantly antiandrogenic actions. In accordance, although produces feminization of and ambiguous genitalia in male fetuses when administered to pregnant animals,[77] it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. Additionally, all, including and spironolactone, have been found to stimulate and significantly accelerate the growth of androgen-sensitive tumors in the absence of androgens, whereas like flutamide have no effect and can in fact antagonize the stimulation caused by .[78] Accordingly, unlike, the addition of to castration has never been found in any controlled study to prolong survival in prostate cancer to a greater extent than castration alone. In fact, a meta-analysis found that the addition of to castration actually reduces the long-term effectiveness of and causes an increase in mortality (mainly due to cardiovascular complications induced by).[79] 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.[80] [81] Because of their intrinsic capacity to activate the, are incapable of maximally depriving the body of androgen signaling, and will always maintain at least some degree of activation.

Due to its progestogenic (and by extension antigonadotropic) activity, is able to suppress circulating testosterone levels by 70 to 80% in men at high dosages.[82] In contrast, increase testosterone levels by up to 2-fold via blockade of the, a difference that is due to their lack of concomitant antigonadotropic action.[83] However, in spite of the combined antagonism and marked suppression of androgen levels by (and hence a sort of profile of antiandrogen action), monotherapy with an,, or a analogue/castration all have about the same effectiveness in the treatment of prostate cancer, whereas in the form of the addition of bicalutamide (but not of) to castration has slightly but significantly greater comparative effectiveness in slowing the progression of prostate cancer and extending life. These differences may be related to the inherent androgenicity of, which likely serves to limit its clinical efficacy as an antiandrogen in prostate cancer.[84]

Tolerability and safety

Due to the different hormonal activities of like bicalutamide and like, they possess different profiles of adverse effects. is regarded as having an unfavorable side effect profile, and the tolerability of bicalutamide is considered to be superior. Due to its strong antigonadotropic effects and suppression of androgen and estrogen levels, is associated with marked sexual dysfunction (including loss of libido and impotence) similar to that seen with castration, and osteoporosis,[85] whereas such side effects occur minimally with like bicalutamide. In addition, has been associated with coagulation changes and thrombosis, fluid retention, cardiovascular side effects (e.g., ischemic cardiomyopathy),[86] [87] and adverse effects on serum lipid profiles, with severe cardiovascular complications occurring in approximately 10% of men with prostate cancer. In contrast, bicalutamide and other are not associated with these adverse effects.[88] Moreover, high doses of are associated with hepatotoxicity,[89] whereas the risk of hepatotoxicity appears to be smaller with bicalutamide.[90] [91] has also been associated with psychological side effects such as depression, fatigue, and irritability.[92] [93] [94] [95]

It has been said that the only advantage of over castration is its relatively low incidence of hot flashes, a benefit that is mediated by its progestogenic activity. Due to increased estrogen levels, bicalutamide and other are similarly associated with low rates of hot flashes (9.2% for bicalutamide vs. 5.4% for placebo in the trial). One advantage of over 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%),[96] [97] whereas are associated with rates of gynecomastia of up to 80%.[98] Although monotherapy has many tolerability advantages in comparison to, a few of these advantages, such as preservation of sexual function and interest and (i.e., no increased incidence of osteoporosis) and low rates of hot flashes, are lost when are combined with castration.[99] However, the risk and severity of gynecomastia with are also greatly diminished in this context.[100]

Unlike spironolactone, bicalutamide has no antimineralocorticoid activity,[101] and for this reason, has no risk of hyperkalemia (which can, rarely/in severe cases, result in hospitalization or death)[102] or other antimineralocorticoid side effects such as urinary frequency, dehydration, hypotension, hyponatremia, metabolic acidosis, or decreased renal function that may occur with spironolactone treatment.[103] [104] [105] In women, unlike and spironolactone,[106] bicalutamide does not produce menstrual irregularity or amenorrhea, nor does it interfere with ovulation.[107] [108]

Castration and analogues

Castration consists of either medical castration with a analogue or surgical castration via orchiectomy. analogues include agonists like leuprorelin or goserelin and antagonists like cetrorelix. They are powerful antigonadotropins and work by abolishing the -induced secretion of gonadotropins, in turn ceasing gonadal production of sex hormones. Medical and surgical castration achieve essentially the same effect, decreasing circulating testosterone levels by approximately 95%.[109]

Effectiveness

Bicalutamide monotherapy has been reported to be roughly equivalent in effectiveness compared to analogues and castration in the treatment of prostate cancer. A meta-analysis concluded that there is a slight effectiveness advantage for analogues/castration, but the differences trended towards but did not reach statistical significance in that study. In, the median survival time was found to be only 6 weeks shorter with bicalutamide monotherapy in comparison to analogue monotherapy.[110] However, a 2015 Cochrane review reported lower overall survival times (= 1.24), greater clinical progression (= 1.14–1.26), and treatment failure (= 1.14–1.27) with monotherapy compared to monotherapy with a agonist or surgical castration.[111]

Tolerability and safety

Monotherapy with 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 analogues, (and analogue combination),, or surgical castration in prostate cancer.[112] [113] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for and 69% reported complete loss of erectile function relative to 93% for . 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.[114] 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.[115] It has been proposed that due to the lower relative effect of on sexual interest and activity, with two-thirds of advanced 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. Also, bicalutamide differs from analogues (which decrease and significantly increase the risk of bone fractures)[116] in that it has well-documented benefits on, effects that are likely due to increased levels of estrogen.[117] [118]

A 2015 Cochrane review found that monotherapy for prostate cancer had a greater risk of treatment discontinuation due to adverse effects than monotherapy with a agonist or surgical castration (= 1.82). This included a greatly increased risk of breast pain (= 22.97) and gynecomastia (= 8.43). The risk of other adverse effects, such as hot flashes (= 0.23), was decreased with monotherapy. The quality of the evidence was deemed moderate.

Notes and References

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