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|Trade names||Casodex, Cosudex, Calutide, Calumid, Kalumid, others|
|Drug class||Nonsteroidal antiandrogen|
|Bioavailability||Well-absorbed; absolute bioavailability unknown|
|Protein binding||Racemate: 96.1%
(Mainly to albumin)
• Hydroxylation (CYP3A4)
• Glucuronidation (UGT1A9)
|Metabolites||• Bicalutamide glucuronide
• Hydroxybicalutamide gluc.
|Biological half-life||Acute: 5.8 days
Chronic: 7–10 days
|Chemical and physical data|
|Molar mass||430.373 g/mol|
|3D model (JSmol)|
|Chirality||Racemic mixture (of (R)- and (S)-enantiomers)|
|Melting point||191 to 193 °C (376 to 379 °F) (experimental)|
|Boiling point||650 °C (1,202 °F) (predicted)|
|Solubility in water||0.005 mg/mL (20 °C)|
|(what is this?)|
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer. Bicalutamide may also be used to treat excessive hair growth in women, as a component of hormone therapy for transgender women, to treat early puberty in boys, and to prevent priapism. It is taken by mouth.
Common side effects in men include breast enlargement, breast tenderness, and hot flashes. Other side effects in men include feminization and sexual dysfunction. While the medication appears to produce few side effects in women, its use in women is not recommended by the Food and Drug Administration (FDA). Use during pregnancy may harm the baby. Bicalutamide causes elevated liver enzymes in around 1% of people. Rarely, it has been associated with cases of liver damage, lung toxicity, and sensitivity to light. Although the risk of adverse liver changes is small, monitoring of liver enzymes is recommended during treatment.
Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications, it works by blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT). It does not lower androgen levels, the medication can have some estrogen-like effects in men. Bicalutamide is well-absorbed, and its absorption is not affected by food, the elimination half-life of the medication is around one week. It is believed to cross the blood–brain barrier and affect both the body and brain.
Bicalutamide was patented in 1982 and approved for medical use in 1995, it is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Bicalutamide is available as a generic medication, the wholesale cost in the developing world is about US$7.07 to US$144.22 per month. In the United States it costs about US$10 and above per month, the drug is sold in more than 80 countries, including most developed countries. It is the most widely used antiandrogen in the treatment of prostate cancer, and has been prescribed to millions of men with the disease.
- 1 Medical uses
- 2 Contraindications
- 3 Side effects
- 3.1 Gynecomastia
- 3.2 Sexual dysfunction
- 3.3 Reproductive changes
- 3.4 Other adverse effects
- 3.5 With castration
- 3.6 Increased mortality
- 3.7 Rare adverse reactions
- 4 Overdose
- 5 Interactions
- 6 Comparison with other antiandrogens
- 6.1 First-generation NSAAs
- 6.2 Second-generation NSAAs
- 6.3 Steroidal antiandrogens
- 6.4 Castration and GnRH analogues
- 7 Pharmacodynamics
- 7.1 Antiandrogenic activity
- 7.2 Other activities
- 8 Pharmacokinetics
- 9 Chemistry
- 10 History
- 11 Society and culture
- 12 Research
- 13 Veterinary use
- 14 References
- 15 Further reading
- 16 External links
- Metastatic prostate cancer (mPC) in men in combination with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy at moderate doses
- Locally advanced prostate cancer (LAPC) in men as a monotherapy in high doses
It can also be and is used to a lesser extent for the following off-label (non-approved) indications:
- Androgen-dependent skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss (androgenic alopecia) in women at low doses, generally in combination with an oral contraceptive
- Hyperandrogenism such as due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH) in women
- Hormone therapy for transgender women in combination with estrogen or alone
- Precocious puberty in boys in moderate doses, especially due to familial male-limited precocious puberty (testotoxicosis)
- Priapism in men at low to very low doses
It has been suggested for but has uncertain effectiveness in the following indications:
- Hypersexuality and paraphilias, particularly in combination with chemical castration
Bicalutamide is used primarily in the treatment of early and advanced prostate cancer, it is approved at a dosage of 50 mg/day as a combination therapy with a GnRH or orchiectomy (that is, surgical or medical castration) in the treatment of stage D2 mPC, and as a monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 LAPC. Although effective in mPC and LAPC, bicalutamide is no longer indicated for the treatment of localized prostate cancer (LPC) due to negative findings in the Early Prostate Cancer (EPC) trial. Prior to the introduction of the newer NSAA enzalutamide in 2012, bicalutamide was considered to be the standard-of-care antiandrogen in the treatment of prostate cancer, and still remains widely used for this indication. Compared to earlier antiandrogens like the steroidal antiandrogen (SAA) cyproterone acetate (CPA) and the NSAAs flutamide and nilutamide, bicalutamide shows an improved profile of effectiveness, tolerability, and safety, and for this reason has largely replaced them in the treatment of prostate cancer.
Role of antiandrogens in prostate cancer
In the early 1940s, it was discovered that growth of prostate cancer in men regressed with surgical castration or high-dose estrogen treatment, which were associated with very low levels of circulating testosterone, and accelerated with the administration of exogenous testosterone. It has since been elucidated that androgens like testosterone and DHT function as trophic factors for the prostate gland, stimulating cell division and proliferation and producing tissue growth and glandular enlargement, which, in the context of prostate cancer, results in stimulation of tumors and a considerable acceleration of disease progression. As a result of these discoveries, androgen deprivation therapy (ADT), via a variety of modalities including surgical castration, high-dose estrogens, SAAs, GnRH analogues, NSAAs, and androgen biosynthesis inhibitors (e.g., abiraterone acetate), has become the mainstay of treatment for prostate cancer. Although ADT can shrink or stabilize prostate tumors and hence significantly slow the course of prostate cancer and prolong life, it is, unfortunately, not generally curative. While effective in slowing the progression of the disease initially, most advanced prostate cancer patients eventually become resistant to ADT and prostate cancer growth starts to accelerate again, in part due to progressive mutations in the AR that result in the transformation of drugs like bicalutamide from AR antagonists to agonists.
A few observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an NSAA are combined. It has been found that very low levels of androgens, as in castration, are able to significantly stimulate growth of prostate cancer cells and accelerate disease progression, although castration ceases production of androgens by the gonads and reduces circulating testosterone levels by about 95%, low levels of androgens continue to be produced by the adrenal glands, and this accounts for the residual levels of circulating testosterone. Moreover, it has been found that prostate gland levels of DHT, which is the major androgen in the prostate, remain at 40 to 50% of their initial values following castration. This has been determined to be due to uptake of circulating weak adrenal androgens like dehydroepiandrosterone (DHEA) and androstenedione (A4) by the prostate and their de novo transformation into testosterone and DHT. As such, a considerable amount of androgen signaling continues within the prostate gland even with castration.
In the past, surgical adrenalectomy and early androgen biosynthesis inhibitors like ketoconazole and aminoglutethimide were successfully employed in the treatment of castration-resistant prostate cancer. However, adrenalectomy is an invasive procedure with high morbidity, ketoconazole and aminoglutethimide have relatively high toxicity, and both treatment modalities require supplementation with corticosteroids, making them in many ways unideal. The development of CAB with NSAAs like bicalutamide and enzalutamide and with newer and more tolerable androgen biosynthesis inhibitors like abiraterone acetate has since allowed for non-invasive, convenient, and well-tolerated therapies that have replaced the earlier modalities.
Subsequent clinical research has found that monotherapy with higher dosages of NSAAs than those used in CAB is roughly equivalent to castration in extending life in men with prostate cancer. Moreover, NSAA monotherapy is overall better tolerated and associated with greater quality of life than is castration, which is thought to be related to the fact that testosterone levels do not decrease with NSAA monotherapy and hence by extension that levels of biologically active and beneficial metabolites of testosterone such as estrogens and neurosteroids are preserved. For these reasons, NSAA monotherapy has become an important alternative to castration and CAB in the treatment of prostate cancer.
Skin and hair conditions
Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male pattern hair loss. Conversely, hyperandrogenism in women, for instance due to PCOS or CAH, is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens have been found to be highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.
Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women in clinical studies. In one of the studies, the drug was well-tolerated, all of the patients experienced a visible decrease in hair density, and a highly significant clinical improvement was observed with the Ferriman–Gallwey score decreasing by 41.2% at 3 months and by 61.6% at 6 months. According to a 2013 review, "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to IH and PCOS. It does not have any significant side effects [or lead] to irregular periods."
In addition to hirsutism, bicalutamide can also be used in the treatment of acne in women. Several studies have observed complete clearing of acne with flutamide in women, and similar benefits would be expected with bicalutamide.:712–717 Bicalutamide may also treat other androgen-dependent skin and hair conditions like seborrhea and pattern hair loss. Flutamide has been found to produce a decrease of hirsutism score to normal and an 80% or greater decrease in scores of acne, seborrhea, and androgen-dependent hair loss. Moreover, in combination with an oral contraceptive, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in 6 of 7 women suffering from pattern hair loss.
Antiandrogens like flutamide and bicalutamide are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects (see below), and for this reason, are not recommended by the FDA for use in women. Because of this risk, it is strongly recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.
Transgender hormone therapy
Bicalutamide is used as a component of hormone replacement therapy (HRT) for transgender women. Beneficial or desired effects consist of demasculinization and feminization, and include breast development, reduced male-pattern hair, decreased muscle mass, feminine changes in fat distribution, lowered libido, and loss of spontaneous erections. It is also noteworthy that, when used as a monotherapy, bicalutamide significantly increases estradiol levels in biological males and hence can have indirect estrogenic effects in transgender women; this is a property that can be considered to be desirable in transgender women, as it can produce or contribute to feminization.
Unlike the SAAs CPA and spironolactone, as well as GnRH analogues, no clinical studies assessing bicalutamide as an antiandrogen in the hormonal therapy of transgender women appear to have been conducted to date. In any case, bicalutamide is clinically effective as an antiandrogen in women with hirsutism and in boys with precocious puberty, and demasculinization and feminization are well-documented effects of bicalutamide in men treated with it for prostate cancer (see below). In addition, nilutamide, a closely related antiandrogen that possesses essentially the same mechanism of action as bicalutamide, has been evaluated in transgender women in at least five small clinical studies. It was given at a high dosage of 300 mg/day, the same dosage in which it has been used as a monotherapy in the treatment of prostate cancer. The corresponding monotherapy dosage of bicalutamide in the treatment of prostate cancer is 150 mg/day.
In the clinical studies of nilutamide for transgender hormone therapy, the drug, without being combined with estrogen, induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks, including breast development, decreased male-pattern hair, decreased spontaneous erections and sex drive, and positive psychological and emotional changes. Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity; along with decreased hair growth, these changes were the earliest signs of feminization. The drug more than doubled luteinizing hormone (LH) and testosterone levels and tripled estradiol levels (see below), and the addition of ethinylestradiol, a potent estrogen, to nilutamide therapy after 8 weeks of treatment abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range. On the basis of these results, both nilutamide alone, and particularly the combination of nilutamide and an estrogen, were regarded as effective in terms of producing antiandrogen effects and feminization in transgender women.
Although nilutamide has been found to be clinically effective for transgender hormone therapy, the use of nilutamide in the treatment of prostate cancer and particularly for other indications that are of a less dire nature is now discouraged due to the unique adverse effects of the drug, most importantly a high incidence of interstitial pneumonitis. This is an adverse effect that can progress to pulmonary fibrosis and can potentially be fatal, for this reason, newer, safer NSAAs like bicalutamide have largely replaced nilutamide and are now used for such indications instead.
Madeline Deutsch of the Center of Excellence for Transgender Health at the University of California, San Francisco, in her Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People (2016), has said the following on the topic of bicalutamide in transgender women:
In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used [as an antiandrogen in feminizing hormone therapy for transgender women]. Cyproterone [acetate] has been associated with uncommon episodes of fulminant hepatitis. Bicalutamide, a direct anti-androgen used for the treatment of prostate cancer, also has a small but not fully quantified risk of liver function abnormalities (including several cases of fulminant hepatitis); while such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, such risks are less justified in the context of gender-affirming treatment. No evidence at present exists to inform such an analysis.
In spite of its risk of hepatotoxicity, CPA is the most widely used antiandrogen in Europe and elsewhere in the world for hormone therapy in transgender women. In addition, it is widely used in cisgender women for the treatment of acne and hirsutism; in the U.S., one of the only countries where CPA has not been approved for medical use, the relatively weak agent spironolactone is the antiandrogen most commonly used in transgender and cisgender women instead. Although both CPA and bicalutamide have been associated with hepatotoxicity (while spironolactone is not usually associated with such), bicalutamide has a far lower and only small risk of both elevated liver enzymes and hepatotoxicity (see below); whereas CPA has been associated with over 100 reports of hepatotoxicity, five cases of hepatotoxicity, out of millions of patient exposures, have been associated with bicalutamide to date.
Male early puberty
Bicalutamide (25–50 mg/day) is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of male precocious puberty. This is potentially a cost-effective alternative to GnRH analogues for the treatment of this condition, as GnRH analogues are very expensive. Moreover, the combination is effective in gonadotropin-independent precocious puberty, namely familial male-limited precocious puberty (also known as testotoxicosis), where GnRH analogues notably are not effective. Bicalutamide has been found to be superior to the SAA spironolactone (which has also been used, in combination with the aromatase inhibitor testolactone) for this indication; it has shown greater effectiveness and possesses fewer side effects in comparison. For this reason, bicalutamide has replaced spironolactone in the treatment of the condition.:2139
Antiandrogens can considerably relieve and prevent priapism (potentially painful penile erections that last more than four hours) via direct blockade of penile ARs. In accordance, bicalutamide, at low dosages (50 mg every other day or as little as once or twice weekly), has been found in a series of case reports to completely resolve recurrent priapism in men without producing significant side effects, and is used for this indication off-label. In the reported cases, libido, rigid erections, the potential for sexual intercourse, orgasm, and subjective ejaculatory volume have all remained intact or unchanged, and gynecomastia has not developed when bicalutamide is administered at a total dosage of 25 mg/day or less. Some gynecomastia and breast tenderness developed in one patient treated with 50 mg/day, but significantly improved upon the dosage being halved. The observed tolerability profile of bicalutamide in these subjects has been regarded as significantly more favorable than that of GnRH analogues and estrogens (which are also used in the treatment of this condition). However, although successful and well-tolerated, very few cases have been reported.
Paraphilias and hypersexuality
The antigonadotropic antiandrogens CPA, medroxyprogesterone acetate (MPA), and GnRH analogues have all been widely used to treat paraphilias (e.g., pedophilia) and hypersexuality in men. They suppress androgen levels to castrate or near-castrate levels and are highly effective in reducing sexual urges, arousal, and behaviors. In addition, they are used to treat sex offenders as a means of chemical castration for the purpose of reducing the likelihood of recidivism.
Although they have not been studied in the treatment of paraphilias and hypersexuality, NSAAs like flutamide and bicalutamide have been suggested as potential medications for these indications and may have superior tolerability and safety relative to antigonadotropic antiandrogens. As an example, because NSAAs do not reduce estrogen levels, unlike antigonadotropic antiandrogens, they preserve bone mineral density (BMD) and have little or no risk of osteoporosis and associated bone fractures. However, due to unopposed estrogen signaling, a substantial incidence of gynecomastia is associated with NSAAs. In addition to potential monotherapy use, NSAAs have been advocated for temporarily suppressing sex drive during the start of GnRH agonist treatment via prevention of the increased androgen signaling associated with the initial testosterone flare.
Though treatment of paraphilias and hypersexuality with selective AR antagonists is a seemingly sound strategy, this may not be true in practice. Surprisingly, little or no sexual dysfunction, including loss of sex drive and decreased sexual activity, has been observed in clinical studies of NSAA monotherapy. The explanation for this is that NSAAs do not lower androgen levels, and metabolites of testosterone like estrogens and neurosteroids may be of critical importance for maintenance of sex drive and function in males. In accordance, testosterone is locally aromatized into estradiol widely throughout the brain and estradiol appears to be the mediator of many of the central actions of testosterone, for these reasons, unlike antigonadotropic antiandrogens, NSAA monotherapy may have limited usefulness in the management of paraphilias and hypersexuality. The addition of NSAAs to antigonadotropic antiandrogens like GnRH analogues may have some usefulness however, particularly in severe cases. In any case, insufficient evidence is available at this time, and further research is thus warranted.
Bicalutamide is available for the treatment of prostate cancer in most developed countries, including over 80 countries worldwide. Bicalutamide is available in 50 mg, 80 mg (in Japan), and 150 mg tablets for oral administration. The drug is registered for use as a 150 mg/day monotherapy for the treatment of LAPC in at least 55 countries, with the U.S. being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration. No other formulations or routes of administration are available or used. All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration. A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP (Zoladex–Cosudex Combination Pack).
In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients; in severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively). The elimination half-life of bicalutamide is unchanged in renal impairment.
Pregnancy and breastfeeding
Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the U.S., and pregnancy category D, the second most restricted rating, in Australia. As such, it is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with adequate contraception, it is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended while breastfeeding.
Because bicalutamide blocks the AR, like all antiandrogens, it can interfere with the androgen-mediated sexual differentiation of the genitalia (and brain) during prenatal development. In pregnant rats given bicalutamide at a dosage of 10 mg/kg/day (resulting in circulating drug levels approximately equivalent to two-thirds of human therapeutic concentrations) and above, feminization of male offspring, such as reduced anogenital distance and hypospadias, as well as impotence, were observed. No other teratogenic effects were observed in rats or rabbits receiving up to very high dosages of bicalutamide (that corresponded to up to approximately two times human therapeutic levels), and no teratogenic effects of any sort were observed in female rat offspring at any dosage, as such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.
The side effect profile of bicalutamide is highly dependent on sex; that is, on whether the person is male or female. In men, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (breast development/enlargement) being the most common. In addition breast changes, physical feminization and demasculinization in general, including reduced body hair growth, decreased muscle mass and strength, feminine changes in fat mass and distribution, and reduced penile length, may also occur in men. Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, anemia, and decreased semen/ejaculate volume. In women, on the other hand, due to the little biological importance of androgens in this sex, the side effects of pure antiandrogens or NSAAs are minimal, and bicalutamide has been found to be very well-tolerated. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash. The drug is well-tolerated at higher dosages than the 50 mg/day dosage, with rare additional side effects.
Bicalutamide monotherapy has been associated with abnormal liver function tests such as elevated liver enzymes in 3.4% of men relative to 1.9% for standard care. Hepatic changes such as marked increases in liver enzymes or hepatitis that necessitated discontinuation of bicalutamide have occurred in approximately 0.3 to 1% of men in clinical trials. Monitoring of liver function during treatment is recommended, particularly in the first few months; in men of advanced age with prostate cancer, bicalutamide monotherapy has been associated with an increase in non-prostate cancer mortality, in part due to an increase in the rate of heart failure. These mortality-related effects are thought to be a consequence of androgen deprivation, rather than a specific drug-related toxicity of bicalutamide.
Five cases of hepatotoxicity or liver failure, two of which resulted in death, have been reported with bicalutamide. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice. Bicalutamide has also been associated with several case reports of interstitial pneumonitis, which can potentially progress to pulmonary fibrosis. Symptoms that may indicate lung dysfunction include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat). Both hepatotoxicity and interstitial pneumonitis are said to be extremely rare events with bicalutamide. A few cases of photosensitivity have been reported with bicalutamide. Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.
The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia, these side effects may occur in as much as 90% of men treated with bicalutamide monotherapy, but gynecomastia is generally reported to occur in 70–80% of patients. In the EPC trial, at a median follow-up of 7.4 years, breast pain and gynecomastia respectively occurred in 73.6% and 68.8% of men treated with 150 mg/day bicalutamide monotherapy. In more than 90% of affected men, bicalutamide-related breast events are mild-to-moderate in severity, it is only rarely and in severe and extreme cases of gynecomastia that the proportions of the male breasts become so marked that they are comparable to those of women. In the EPC trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia. The incidence and severity of gynecomastia are higher with estrogens (e.g., diethylstilbestrol) than with NSAAs like bicalutamide in the treatment of men with prostate cancer.
Tamoxifen, a selective estrogen receptor modulator (SERM) with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be highly effective in preventing and reversing bicalutamide-induced gynecomastia in men. Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis. For reasons that are unclear, anastrozole, an aromatase inhibitor (or an inhibitor of estrogen biosynthesis), has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia. A systematic review of NSAA-induced gynecomastia and breast tenderness concluded that tamoxifen (10–20 mg/day) and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness. Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.
Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction. However, the rates of these side effects with bicalutamide monotherapy are very low; in the EPC trial, at 7.4 years follow-up, the rates of decreased libido and impotence were only 3.6% and 9.3% in the 150 mg/day bicalutamide monotherapy group relative to 1.2% and 6.5% for placebo, respectively. Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs. In clinical trials, about two-thirds of men with advanced prostate cancer (and of almost invariably advanced age) treated with bicalutamide monotherapy maintained sexual interest, while sexual function was slightly reduced by 18%.
Similarly to men, bicalutamide is likely to be associated with minimal or no sexual dysfunction in women. Studies have not found a significant correlation between libido and circulating testosterone levels in premenopausal women, and treatment of premenopausal women with low doses of testosterone has not been found to improve sexual function in most research. However, low-dose testosterone therapy has been found to significantly improve multiple domains of sexual function (frequency, libido, orgasm, satisfaction, others) in postmenopausal women, particularly in those who have undergone ovariectomy. Conversely, women with PCOS, who have higher levels of testosterone, do not show increased sex drive, and treatment with oral contraceptives, which contain estrogen and decrease free testosterone levels, have been found not to decrease sexual function but to increase it in both healthy women and those with PCOS; in addition, women with CAIS show normal or even increased sexual function in spite of complete loss of AR signaling. It has been suggested that increased sex drive and sexual function associated with testosterone may be mediated by aromatization into estradiol rather than necessarily via activation of the AR.
Bicalutamide reduces the size of the prostate gland and seminal vesicles, though not of the testes. Significantly reduced penile length is also a recognized adverse effect of ADT. Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur. However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men (see below). Due to the induction of chronic overproduction of LH and testosterone, there was concern that long-term bicalutamide monotherapy might induce Leydig cell hyperplasia and tumors (usually benign), but the evidence indicates that Leydig cell hyperplasia does not occur to a significant extent.
Other adverse effects
The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively). In phase III studies of bicalutamide monotherapy for LAPC, the rates of diarrhea for bicalutamide and castration were 6.4% and 12.5%, respectively, the rates of constipation were 13.7% and 14.4%, respectively, and the rates of abdominal pain were 10.5% and 5.6%, respectively.
In the EPC trial, at 7.4 years follow-up, the rate of hot flashes was 9.2% for bicalutamide relative to 5.4% for placebo, which was regarded as relatively low. In the LAPC subgroup of the EPC trial, the rate of hot flashes with bicalutamide was 13.1% (relative to 50.0% for castration).
At 5.3 years follow-up, the incidence of depression was 5.5% for bicalutamide relative to 3.0% for placebo in the EPC trial, and the incidence of asthenia (weakness or fatigue) was 10.2% for bicalutamide relative to 5.1% for placebo.
Androgens are known to stimulate the formation of red blood cells and increase the red blood cell count and circulating hematocrit levels, effects which they mediate by increasing production of erythropoietin in the kidneys. In accordance, anabolic–androgenic steroids (AAS) such as oxymetholone and nandrolone decanoate are approved and used in the treatment of severe anemia, and AAS can cause polycythemia as an adverse effect in high dosages. Conversely, whether via castration, NSAA monotherapy, or CAB, mild anemia is a common side effect of ADT in men. The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials. A decrease of hemoglobin levels of 1–2 g/dL after approximately six months of treatment may be observed.
Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes. Skin-related side effects, which included dry skin, itching, and rash, were reported at a rate of 2% in both monotherapy and CAB clinical studies of bicalutamide in men.
Combination of bicalutamide with medical (i.e., a GnRH analogue) or surgical castration modifies the side effect profile of bicalutamide. Some of its side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when the drug is combined with a GnRH analogue, while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction, occur much more frequently in combination with a GnRH analogue. It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogen may compensate for various negative central effects of androgen deprivation. If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels in men caused by bicalutamide will be prevented and the side effects of excessive estrogens, namely gynecomastia, will be reduced. However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.
In the LPC group of the EPC study, although 150 mg/day bicalutamide monotherapy had reduced mortality due to prostate cancer relative to placebo, there was a trend toward significantly increased overall mortality for bicalutamide relative to placebo at 5.4-year follow-up (25.2% vs. 20.5%). This was because more bicalutamide than placebo recipients had died due to causes unrelated to prostate cancer in this group (16.8% vs. 9.5% at 5.4-year follow-up; 10.2% vs. 9.2% at 7.4-year follow-up). At 7.4-year follow-up, there were numerically more deaths from heart failure (1.2% vs. 0.6%; 49 vs. 25 patients) and gastrointestinal cancer (1.3% vs. 0.9%) in the bicalutamide group relative to placebo recipients, although cardiovascular morbidity was similar between the two groups and there was no consistent pattern suggestive of drug-related toxicity for bicalutamide. In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated, it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation. In this regard, it is notable that low testosterone levels in men have been associated in epidemiological studies with cardiovascular disease as well as with a variety of other disease states (including hypertension, hypercholesterolemia, diabetes, obesity, Alzheimer's disease, osteoporosis, and frailty).
According to Iversen et al. (2006), the increased non-prostate cancer mortality with bicalutamide monotherapy in LPC patients has also been seen with castration (via orchiectomy or GnRH analogue monotherapy) and is likely a consequence of androgen deprivation in men rather than a specific drug toxicity of bicalutamide:
The increased number of deaths in patients with localized disease receiving bicalutamide was meticulously investigated and they appeared to be due to a number of small imbalances rather than a specific cause. In addition, no direct toxic effect on any organ system could be identified, from this it may be speculated that the excess deaths in patients who are at low risk from prostate cancer mortality reflect the impact of endocrine therapy (rather than bicalutamide in particular). [...] The increased number of non-prostate cancer deaths in the early castration therapy arm [(via orchiectomy or GnRH monotherapy)] in the [Medical Research Council] study suggests that the trend towards an increased number of deaths in patients with localized disease in the present study is a reflection of early endocrine therapy as a concept rather than a bicalutamide-related phenomenon.
A meta-analysis of prospective, randomized clinical trials of GnRH agonist-based ADT for the treatment of non-metastatic prostate cancer that included over 4,000 patients found no evidence of increased cardiovascular mortality or overall mortality. Non-prostate cancer mortality was not specifically assessed.
Rare adverse reactions
Bicalutamide may cause liver changes rarely, such as elevated transaminases and jaundice; in the EPC study of 4,052 prostate cancer patients who received 150 mg/day bicalutamide as a monotherapy, the incidence of abnormal liver function tests was 3.4% for bicalutamide and 1.9% for standard care (a 1.5% difference potentially attributable to bicalutamide) at 3-year median follow-up. For comparison, the incidences of abnormal liver function tests are 42–62% for flutamide, 2–3% for nilutamide, and (dose-dependently) between 9.6% and 28.2% for CPA, whereas there appears to be no risk with enzalutamide. In the EPC trial, bicalutamide-induced liver changes were usually transient and rarely severe. The drug was discontinued due to liver changes (manifested as hepatitis or marked increases in liver enzymes) in approximately 0.3% to 1% of patients treated with it for prostate cancer in clinical trials.
The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended. Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued. Liver changes with bicalutamide usually occur within the first 3 or 4 months of treatment, and it is recommended that liver function be monitored regularly for the first 4 months of treatment and periodically thereafter. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.
Out of millions of patient exposures, a total of five cases of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been reported in the medical literature as of 2016. One of these cases occurred after only two doses of bicalutamide, and has been regarded as much more likely to have been caused by prolonged prior exposure of the patient to flutamide and CPA. In the five reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50 mg/day (three), 100 mg/day (one), and 150 mg/day (one). Relative to flutamide (which has an estimated incidence rate of 3 in every 10,000), hepatotoxicity is far rarer with bicalutamide and nilutamide, and bicalutamide is regarded as having the lowest risk of the three drugs. For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death. Moreover, a 2002 review reported that there were 18 reports of hepatotoxicity associated with CPA in the medical literature, with 6 of the reported cases resulting in death, and the review also cited a report of an additional 96 instances of hepatotoxicity that were attributed to CPA, 33 of which resulted in death.
The clinical studies that have found elevated liver enzymes and the case reports of hepatotoxicity with bicalutamide have all specifically pertained to men of advanced age with prostate cancer. It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity, as such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women. However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.
From a theoretical standpoint (on the basis of structure–activity relationships), it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause liver toxicity. However, in contrast to flutamide, hydroxyflutamide, and nilutamide, bicalutamide exhibits much less or no mitochondrial toxicity and inhibition of enzymes in the electron transport chain such as respiratory complex I (NADH ubiquinone oxidoreductase), and this may be the reason for its much lower risk of hepatotoxicity in comparison. The activity difference may be related to the fact that flutamide, hydroxyflutamide, and nilutamide all possess a nitroaromatic group, whereas in bicalutamide, a cyano group is present in place of this nitro group, potentially reducing toxicity.
Several case reports of interstitial pneumonitis (which can progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature. Interstitial pneumonitis with bicalutamide is said to be an extremely rare event, and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).:81 In a very large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was 0.77% for nilutamide but only 0.04% for flutamide and 0.01% for bicalutamide. An assessment done prior to the publication of the aforementioned study estimated the rates of pulmonary toxicity with flutamide, bicalutamide, and nilutamide as 1 case, 5 cases, and 303 cases per million, respectively; in addition to interstitial pneumonitis, a single case report of eosinophilic lung disease in association with six months of 200 mg/day bicalutamide treatment exists. Side effects associated with the rare potential pulmonary adverse reactions of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).
Sensitivity to light
A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported. In one of the cases, bicalutamide was continued due to effectiveness in treating prostate cancer in the patient, and in combination with strict photoprotection (in the form of avoidance/prevention of ultraviolet light exposure), the symptoms disappeared and did not recur. Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.
Male breast cancer
A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published. According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)." It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men. Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%, the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years), and millions of men have been treated with bicalutamide for prostate cancer, all of which are potentially in support of the notion of chance co-occurrences. In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."
A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established. Dosages of up to 600 mg/day have been well-tolerated in clinical trials, and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day. Overdose is considered to be unlikely to be life-threatening with bicalutamide or other first-generation NSAAs (i.e., flutamide and nilutamide). A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs or symptoms or toxicity. There is no specific antidote for bicalutamide or NSAA overdose, and treatment should be based on symptoms.
Cytochrome P450 enzymes
Bicalutamide is almost exclusively metabolized by CYP3A4, as such, its levels in the body may be altered by inhibitors and inducers of CYP3A4. (For a list of CYP3A4 inhibitors and inducers, see here.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or induce cytochrome P450 enzyme activity.
Plasma binding proteins
Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs like warfarin, phenytoin, theophylline, and aspirin from plasma binding proteins. This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments. Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins (namely albumin) in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs. However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.
Comparison with other antiandrogens
Since their introduction, bicalutamide and the other NSAAs have largely replaced CPA, an older drug and an SAA, in the treatment of prostate cancer. Bicalutamide was the third NSAA to be marketed, with flutamide and nilutamide preceding, and followed by enzalutamide. 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. For these reasons, as well as superior potency, tolerability, and pharmacokinetics, bicalutamide is preferred and has largely replaced flutamide and nilutamide in clinical practice. In accordance, bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer. Between January 2007 and December 2009, it accounted in the U.S. for about 87.2% of NSAA prescriptions. Prior to the 2012 approval of enzalutamide, a newer and improved NSAA with greater potency and efficacy, bicalutamide was regarded as the standard-of-care antiandrogen in the treatment of the prostate cancer.
|Half-life||5–6 hours||~2 days||~7 days|
|Dosage||250 mg t.i.d.||100 mg t.i.d.||150 mg o.d.|
|• Nausea and vomiting
• Visual disturbances
• Alcohol intolerance
• Interstitial pneumonitis
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. However, bicalutamide is the most potent of the three, with the highest affinity for the AR and the longest elimination half-life, and is the safest, least toxic, and best-tolerated. For these reasons, bicalutamide has largely replaced flutamide and nilutamide in clinical use, and is by far the most widely used first-generation NSAA.
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), and 5-fold higher affinity relative to that of nilutamide. In addition, bicalutamide possesses the longest elimination half-life of the three drugs, with half-lives of 6–10 days for bicalutamide, 5–6 hours for flutamide and 8–9 hours for hydroxyflutamide, 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, for this reason, dosing of bicalutamide (and nilutamide) is more convenient than with flutamide. 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.
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. 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
|–: Not reported; +: ≥ 1%, < 20%; ++: ≥ 20%, < 40%; +++: ≥ 40%|
The core side effects of NSAAs such as gynecomastia, sexual dysfunction, and hot flashes occur at similar rates with the different drugs. Conversely, bicalutamide is associated with a significantly lower rate of diarrhea compared to flutamide; in fact, the incidence of diarrhea did not differ between the bicalutamide and placebo groups (6.3% vs. 6.4%, respectively) in the EPC trial, 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); 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. In contrast to flutamide and nilutamide, no specific complications have been linked to bicalutamide.
Enzalutamide, along with the in-development apalutamide and darolutamide, are newer, second-generation NSAAs. Similarly to bicalutamide and the other first-generation NSAAs, they possess the same core mechanism of action of selective AR antagonism, but are considerably more potent and efficacious in comparison.
In comparison to bicalutamide, enzalutamide has 5- to 8-fold higher affinity for the AR, possesses mechanistic differences resulting in improved AR deactivation, shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity, and has an even longer elimination half-life (8–9 days versus ~6 days for bicalutamide). In accordance, enzalutamide, at a dosage of 160 mg/day, has been found to produce similar increases in testosterone, estradiol, and LH levels relative to high-dosage bicalutamide (300 mg/day), and an almost two-fold higher increase in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%). These findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison. Moreover, the drug has demonstrated superior clinical effectiveness in the treatment of prostate cancer in a direct head-to-head comparison with bicalutamide.
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. 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. 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), whereas drug interactions are few and minimal with bicalutamide.
SAAs include CPA, megestrol acetate, chlormadinone acetate, and spironolactone. These drugs are steroids, and similarly to NSAAs, act as competitive antagonists of the AR, reducing androgenic activity in the body.: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. 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. Of the SAAs, CPA is the only one that has been widely used in the treatment of prostate cancer.: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. 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 HRT for transgender women.:1195–6
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. 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. This difference in effectiveness in men and women may be related to the fact that NSAAs like flutamide significantly increase androgen levels in men, which counteracts their antiandrogen potency, but do not increase androgen levels in women. (In contrast to NSAAs, CPA, 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, and is considered to be the most powerful antiandrogen of the three first-generation NSAAs. 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. 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. 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.
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. In accordance, although CPA produces feminization of and ambiguous genitalia in male fetuses when administered to pregnant animals, it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. 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. 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. 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). 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, 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.
Due to its progestogenic (and by extension antigonadotropic) activity, CPA is able to suppress circulating testosterone levels by 70–80% in men at high dosages. 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. 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, 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. 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.
Tolerability and safety
Due to the different hormonal activities of NSAAs like bicalutamide and SAAs like CPA, they possess different profiles of adverse effects. CPA 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, CPA is associated with severe sexual dysfunction (including loss of libido and impotence) similar to that seen with castration, and osteoporosis, whereas such side effects occur little or not at all with NSAAs like bicalutamide. In addition, CPA is associated with coagulation changes and thrombosis (5%), fluid retention (4%), cardiovascular side effects (e.g., ischemic cardiomyopathy) (4–40%), and adverse effects on serum lipid profiles, with severe cardiovascular complications (sometimes being fatal) occurring in approximately 10% of patients. In contrast, bicalutamide and other NSAAs are not associated with these adverse effects. Moreover, CPA has a relatively high rate of generally severe and potentially fatal hepatotoxicity (see here), whereas the risk of hepatotoxicity is far smaller and comparatively minimal with bicalutamide (though not necessarily with other NSAAs, namely flutamide) (see here). CPA has also been associated with high rates of depression (20–30%) and other mental side effects such as fatigue, irritability, anxiety, and suicidal thoughts in both men and women, side effects which may be related to vitamin B12 deficiency.
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. 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). 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%), whereas NSAAs are associated with rates of gynecomastia of up to 80%. 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. However, the risk and severity of gynecomastia with NSAAs are also greatly diminished in this context.
Unlike spironolactone, bicalutamide has no antimineralocorticoid activity, and for this reason, has no risk of hyperkalemia (which can, rarely/in severe cases, result in hospitalization or death) or other antimineralocorticoid side effects such as urinary frequency, dehydration, hypotension, hyponatremia, metabolic acidosis, or decreased renal function that may occur with spironolactone treatment. In women, unlike CPA and spironolactone, bicalutamide does not produce menstrual irregularity or amenorrhea, nor does it interfere with ovulation.
Castration and GnRH analogues
Castration consists of either medical castration with a GnRH analogue or surgical castration via orchiectomy. GnRH analogues include GnRH agonists like leuprorelin or goserelin and GnRH antagonists like cetrorelix. They are powerful antigonadotropins and work by abolishing the GnRH-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%.
Bicalutamide monotherapy has overall been found to be equivalent in effectiveness compared to GnRH analogues and castration in the treatment of prostate cancer. A meta-analysis concluded that there is a slight effectiveness advantage for GnRH analogues/castration, but the differences trend towards but do not reach statistical significance. In mPC, the median survival time was found to be only 6 weeks shorter with bicalutamide monotherapy in comparison to GnRH analogue monotherapy.
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. 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. 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. 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. 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. Also, bicalutamide differs from GnRH analogues (which decrease BMD and significantly increase the risk of bone fractures) in that it has well-documented benefits on BMD, effects that are likely due to increased levels of estrogen.
Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 159–243 nM). It has no capacity to activate the AR under normal physiological circumstances (see below). In addition to competitive antagonism of the AR, bicalutamide has been found to accelerate the degradation of the AR, and this action may also be involved in its activity as an antiandrogen. The activity of bicalutamide lies in the (R)-isomer, which binds to the AR with an affinity that is about 30-fold higher than that of the (S)-isomer. Levels of the (R)-isomer also notably are 100-fold higher than those of the (S)-isomer at steady-state.
Owing to its selectivity for the AR, unlike SAAs such as CPA and megestrol acetate, bicalutamide does not bind to other steroid hormone receptors, and for this reason, has no additional, off-target hormonal activity (estrogenic or antiestrogenic, progestogenic or antiprogestogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid); nor does it inhibit 5α-reductase. However, it significantly increases estrogen levels secondary to blockade of the AR in males, and for this reason, does have some indirect estrogenic effects in men. Also in contrast to SAAs, bicalutamide neither inhibits nor suppresses androgen production in the body (i.e., it does not act as an antigonadotropin or steroidogenesis inhibitor), and instead exclusively mediates its antiandrogen effects by blocking androgen binding and subsequent receptor activation at the level of the AR.
In addition to the classical nuclear AR, bicalutamide has also been identified as a potent antagonist of ZIP9, a membrane androgen receptor (mAR) and zinc transporter protein, with an IC50 of 66.3 nM (relative to Kd = 17.9 nM for testosterone). This protein appears to be involved in protate cancer and breast cancer. Bicalutamide failed to affect testosterone signaling mediated by GPRC6A, another mAR, on the other hand.
Drug levels, androgen levels, and efficacy
Although the affinity of bicalutamide for the AR is approximately 50 times lower than that of DHT (IC50 ≈ 3.8 nM), the main endogenous ligand of the receptor in the prostate gland, sufficiently high relative concentrations of bicalutamide (1,000-fold excess) are effective in preventing activation of the AR by androgens like DHT and testosterone and subsequent upregulation of the transcription of androgen-responsive genes. At steady-state, relative to the normal adult male range for testosterone levels (300–1,000 ng/dL), circulating concentrations of bicalutamide at 50 mg/day are 600 to 2,500 times higher and at 150 mg/day 1,500 to 8,000 times higher than circulating testosterone levels, while bicalutamide concentrations, relative to the mean testosterone levels present in men who have been surgically castrated (15 ng/dL), are 42,000 times higher than testosterone levels at 50 mg/day.
Whereas testosterone is the major circulating androgen, DHT is the major androgen in the prostate gland. DHT levels in circulation are relatively low and only approximately 10% of those of circulating testosterone levels. Conversely, local concentrations of DHT in the prostate gland are 5- to 10-fold higher than circulating levels of DHT. This is due to high expression of 5α-reductase in the prostate gland, which very efficiently catalyzes the formation of DHT from testosterone such that over 90% of intraprostatic testosterone is converted into DHT. Relative to testosterone, DHT is 2.5- to 10-fold as potent as an AR agonist in bioassays, and hence, is a much stronger androgen in comparison. As such, AR signaling is exceptionally high in the prostate gland, and the effectiveness of bicalutamide monotherapy in the treatment of prostate cancer, which is roughly equivalent to that of GnRH analogues, is a reflection of its capacity to strongly and efficaciously antagonize the AR at clinically used dosages. On the other hand, GnRH analogues achieve only a 50 to 60% reduction in levels of DHT in the prostate gland, and the combination of a GnRH analogue and bicalutamide is significantly more effective than either modality alone in the treatment of prostate cancer.
In women, total testosterone levels are 20-fold and free testosterone levels 40-fold lower relative to men; in addition, whereas bicalutamide monotherapy can increase testosterone levels by up to 2-fold in men, the drug does not increase testosterone levels in women (see below). For these reasons, much lower dosages of bicalutamide (e.g., 25 mg/day in the hirsutism studies) may be used in women with comparable antiandrogen effectiveness.
Influences on hormone levels
In men, blockade of the AR by bicalutamide in the pituitary gland and hypothalamus prevents the negative feedback of androgens on the release of LH, resulting in an elevation in LH levels. Follicle-stimulating hormone (FSH) levels, in contrast, remain essentially unchanged. The increase in LH levels leads to an increase in androgen and estrogen levels. At a dosage of 150 mg/day, bicalutamide has been found to increase testosterone levels by about 1.5- to 2-fold (59–97% increase) and estradiol levels by about 1.5- to 2.5-fold (65–146% increase). Levels of DHT are also increased to a lesser extent (by 25%), and concentrations of sex hormone-binding globulin (SHBG) and prolactin increase as well (by 8% and 40%, respectively) secondary to the increase in estradiol levels. The estradiol concentrations produced in men by bicalutamide monotherapy are said to approximate the low-normal estradiol levels of a premenopausal woman, while testosterone levels generally remain in the high end of the normal male range and rarely exceed it. Dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found to produce a "moderate" effect on sex hormone levels in men with prostate cancer (notably providing indication that the drug has clinically-relevant antiandrogen effects in males at a dosage as low as 10 mg/day). It is important to note that bicalutamide increases androgen and estrogen levels only in men and not in women; this is because androgen levels are comparatively far lower in women and in turn exert little to no basal suppression of the hypothalamic–pituitary–gonadal (HPG) axis.
The reason that testosterone levels are elevated but almost always remain in the normal male range with bicalutamide monotherapy is thought to be due to the concomitantly increased levels of estradiol, as estradiol is potently antigonadotropic and limits secretion of LH. In fact, estradiol is a much stronger inhibitor of gonadotropin secretion than is testosterone, and even though circulating concentrations of estradiol are far lower than those of testosterone in men, it is said that estradiol is nonetheless likely the major feedback regulator of gonadotropin secretion in this sex; in accordance, clomifene, a SERM with antiestrogenic activity, has been found to increase testosterone levels to as much as 250% of initial values in men with hypogonadism, and a study of clomifene treatment in normal men observed increases in FSH and LH levels of 70–360% and 200–700%, respectively, with increases in testosterone levels that were similar to the increases seen with the gonadotropins. In addition to systemic or circulating estradiol, local aromatization of testosterone into estradiol in the hypothalamus and pituitary gland may contribute to suppression of gonadotropin secretion.
Bicalutamide more than blocks the effects of the increased testosterone levels that it induces in men, which is evidenced by the fact that monotherapy with the drug is about as effective as GnRH analogue therapy in the treatment of prostate cancer. However, in contrast, the effects of the elevated estrogen levels remain unopposed by bicalutamide, and this is largely responsible for the feminizing side effects (e.g., gynecomastia) of the drug in men.
Differences from castration
It has been proposed that the increase in estrogen levels caused by NSAAs like bicalutamide compensates for androgen blockade in the brain, which may explain differences in the side effect profiles of these drugs relative to GnRH analogues/castration, CAB, and CPA (which, in contrast, decrease both androgen and estrogen levels). In the case of sexual interest and function, this notion is supported by a variety of findings including animal studies showing that estrogen deficiency results in diminished sexual behavior, treatment with tamoxifen resulting in significantly lowered libido in 30% of men receiving it for male breast cancer, and estrogen administration restoring libido and the frequency of sexual intercourse in men with congenital estrogen deficiency, among others.
Several metabolites of testosterone and DHT, including estradiol, 3α-androstanediol, and 3β-androstanediol, are estrogens (mainly potent ERβ agonists in the cases of the latter two), and 3α-androstanediol is additionally a potent GABAA receptor-potentiating neurosteroid. Due to the fact that bicalutamide does not lower testosterone levels, the levels of these metabolites would not be expected to be lowered either, unlike with therapies such as GnRH analogues. (Indeed, testosterone, DHT, and estradiol levels are actually raised by bicalutamide treatment, and for this reason, levels of 3α- and 3β-androstanediol might be elevated to some degree similarly.) These metabolites of testosterone have been found to have AR-independent positive effects on sexual motivation, and may explain the preservation of sexual interest and function by bicalutamide and other NSAAs. They also have antidepressant, anxiolytic, and cognitive-enhancing effects, and may account for the lower incidence of depression with bicalutamide and other NSAAs relative to other antiandrogen therapies.
Paradoxical stimulation of late-stage prostate cancer
Though a pure, or silent antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of AR overexpression and agonist activity in the case of certain mutations in the ligand-binding domain (LBD) of the AR. As both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens, this is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth. The newer drug enzalutamide has been shown not to have agonistic properties in the context of overexpression of the AR, though certain mutations in the AR can still convert it from an antagonist to agonist.
Induction of breast development
In transgender women, breast development is a desired effect of antiandrogen and/or estrogen treatment. Bicalutamide induces breast development (or gynecomastia) in biologically male individuals by two mechanisms: 1) blocking androgen signaling in breast tissue; and 2) increasing estrogen levels. Estrogen is responsible for the induction of breast development under normal circumstances, while androgens powerfully suppress estrogen-induced breast growth, it has been found that very low levels of estrogen can induce breast development in the presence of low or no androgen signaling. In accordance, bicalutamide not only induces gynecomastia at a high rate when given to men as a monotherapy, it results in a higher incidence of gynecomastia in combination with a GnRH analogue relative to GnRH analogue treatment alone (in spite of the presence of only castrate levels of estrogen in both cases).
A study of men treated with NSAA (flutamide or bicalutamide) monotherapy for prostate cancer found that NSAAs induced full ductal development and moderate lobuloalveolar development of the breasts from a histological standpoint. The study also found that, in contrast, treatment of transgender women with estrogen and CPA (which is progestogenic in addition to antiandrogenic, unlike NSAAs) resulted in full lobuloalevolar development, as well as pregnancy-like breast hyperplasia in two of the subjects. In addition, it was observed that the lobuloalveolar maturation reversed upon discontinuation of CPA after sex reassignment surgery (that is, surgical castration) in these individuals. It was concluded that progestogen in addition to antiandrogen/estrogen treatment is required for the induction of full female-like histological breast development (i.e., that includes complete lobuloalveolar maturation), and that continued progestogen treatment is necessary to maintain such maturation. It should be noted however that although these findings may have important implications in the contexts of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue), and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a form of epithelial tissue) contributes to breast size and/or shape.
Effects on spermatogenesis and fertility
Spermatogenesis and male fertility are dependent on FSH, LH, and high levels of testosterone within the testicles. LH does not seem to be involved in spermatogenesis outside of its role in inducing production of testosterone by the Leydig cells in the seminiferous tubules (which make up approximately 80% of the bulk of the testes), whereas this is not the case for FSH, which is importantly involved. In accordance with the fact that the testes are the source of 95% of circulating testosterone in the body, local levels of testosterone inside of the testes are extremely high, ranging from 20- to 200-fold higher than circulating concentrations. Moreover, high levels of testosterone within the testes are required for spermatogenesis, although only a small fraction (5–10%) of normal levels appears to actually be necessary for spermatogenesis.
Unlike with antigonadotropic antiandrogens like CPA and GnRH analogues, it has been reported that bicalutamide monotherapy (at 50 mg/day) has very little effect on the ultrastructure of the testes and on sperm maturation in humans even after long-term therapy (>4 years). This may be explained by the extremely high local levels of testosterone in the testes, in that it is likely that systemic bicalutamide therapy is unable to achieve concentrations of the drug within the testes that are able to considerably block androgen signaling in this part of the body, this is particularly so considering that bicalutamide increases circulating testosterone levels, and by extension gonadal testosterone production, by up to two-fold in males, and that only a small fraction of normal intratesticular testosterone levels, and by extension androgen action, appears to be necessary to maintain spermatogenesis.
In contrast to bicalutamide and other pure antiandrogens or NSAAs, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by FSH, resulting in atrophy and loss of their function. As such, bicalutamide and other NSAAs may uniquely have the potential to preserve testicular function and spermatogenesis and thus male fertility relative to alternative therapies. In accordance with this notion, a study found that prolonged, high-dose bicalutamide treatment had minimal effects on fertility in male rats. However, another study found that low-dose bicalutamide administration resulted in testicular atrophy and reduced the germ cell count in the testes of male rats by almost 50%, though the rate of successful fertilization and pregnancy following mating was not assessed.
Treatment of men with exogenous testosterone or other AAS results in suppression of gonadotropin secretion and gonadal testosterone production due to their antigonadotropic effects or activation of the AR in the pituitary gland, resulting in inhibition or abolition of spermatogenesis and fertility:
Treatment of an infertile man with testosterone does [not] improve spermatogenesis, since exogenous administrated testosterone and its metabolite estrogen will suppress both GnRH production by the hypothalamus and luteinizing hormone production by the pituitary gland and subsequently suppress testicular testosterone production. Also, high levels of testosterone are needed inside the testis and this can never be accomplished by oral or parenteral administration of androgens. Suppression of testosterone production by the leydig cells will result in a deficient spermatogenesis, as can be seen in men taking anabolic–androgenic steroids.
In contrast, pure AR antagonists would, in theory, result in the opposite (although reduced semen volume and sexual dysfunction may occur):
It is theoretically a sound hypothesis that the spermatogenesis can be increased by indirectly stimulating FSH and LH secretions from the pituitary gland. However, for this to fructify, it requires the use of testosterone antagonist to nullify the negative feedback effect of circulating testosterone on the release of FSH and LH, thus augmenting the secretion of testosterone and spermatogenesis. Unfortunately, a testosterone antagonist will be unacceptable to males, as it may reduce secondary sexual functions including erection and ejaculation that is vital for the successful fertilization.
Although bicalutamide alone would appear to have minimal detrimental effect on spermatogenesis and male fertility, other hormonal agents that bicalutamide may be combined with, including GnRH analogues and particularly estrogens (as in transgender hormone therapy), can have a considerable detrimental effect on fertility. This is largely a consequence of their antigonadotropic activity. Antigonadotropic agents like high-dose CPA, high-dose androgens (e.g., testosterone esters), and GnRH antagonists (though notably not GnRH agonists) produce hypogonadism and high rates of severe or complete infertility (e.g., severe oligospermia or complete azoospermia) in men. However, these effects are fully and often rapidly reversible with their discontinuation, even after prolonged treatment; in contrast, while estrogens at sufficiently high dosages similarly are able to produce hypogonadism and to abolish or severely impair spermatogenesis, this is not necessarily reversible in the case of estrogens and can be long-lasting after prolonged exposure. The difference is attributed to an apparently unique, direct adverse effect of high concentrations of estrogens on the Leydig cells of the testes.
Cytochrome P450 modulation
It has been reported that bicalutamide may have the potential to inhibit the enzymes CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6, based on in vitro research. However, no relevant inhibition of CYP3A4 has been observed in vivo with bicalutamide at a dose of 150 mg (using midazolam as a specific marker of CYP3A4 activity). In animals, bicalutamide has been found to be an inducer of certain cytochrome P450 enzymes. However, dosages of 150 mg/day or less have shown no evidence of this in humans.
Bicalutamide has been identified as a strong CYP27A1 (cholesterol 27-hydroxylase) inhibitor in vitro. CYP27A1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions including direct, tissue-specific activation of the estrogen receptor (ER) (it has been characterized as a selective estrogen receptor modulator) and the liver X receptor. 27-Hydroxycholesterol has been found to increase ER-positive breast cancer cell growth via its estrogenic action, and hence, it has been proposed that bicalutamide and other CYP27A1 inhibitors may be effective as adjuvant therapies to aromatase inhibitors in the treatment of ER-positive breast cancer. In addition to CYP27A1, bicalutamide has been found to bind to and inhibit CYP46A1 (cholesterol 24-hydroxylase) in vitro, but this has yet to be assessed and confirmed in vivo.
Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of P-glycoprotein efflux and ATPase activity. This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.
GABAA receptor negative modulation
All of the NSAAs approved for the treatment of prostate cancer have been found to possess an off-target action of acting as weak non-competitive inhibitors of human GABAA receptor currents in vitro to varying extents. The IC50 values are 44 μM for flutamide (as hydroxyflutamide), 21 μM for nilutamide, 5.2 μM for bicalutamide, and 3.6 μM for enzalutamide. In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficiently high doses. Bicalutamide was notably not found to do this, but this was likely simply due to the limited central nervous system penetration of bicalutamide in this species; in any case, enzalutamide is the only approved NSAA that has been found to be associated with a significantly increased incidence of seizures and other associated side effects clinically, so the relevance of the aforementioned findings with regard to bicalutamide and the other NSAAs is unclear.
The pharmacokinetics of bicalutamide are unaffected by food, age, body weight, renal impairment, and mild-to-moderate hepatic impairment. However, it has been observed that steady-state concentrations of bicalutamide are higher in Japanese individuals than in Caucasians, indicating that ethnicity may be associated with differences in the pharmacokinetics of bicalutamide in some instances.
Bicalutamide is extensively and well-absorbed following oral administration, and its absorption is not affected by food, the absolute bioavailability of bicalutamide in humans is unknown due to its very low water solubility and hence lack of an assessable intravenous formulation. However, the absolute bioavailability of bicalutamide has been found to be high in animals at low doses (72% in rats at 1 mg/kg; 100% in dogs at 0.1 mg/kg), but diminishes with increasing doses such that the bioavailability of bicalutamide is low at high doses (10% in rats at 250 mg/kg; 31% in dogs at 100 mg/kg). In accordance, absorption of (R)-bicalutamide in humans is slow and extensive but saturable, with steady-state levels increasing linearly at a dosage of up to 50 mg/day and non-linearly at higher dosages.
At higher dosages of 100 to 200 mg/day, absorption of bicalutamide is approximately linear, with a small but increasing departure from linearity above 150 mg/day. In terms of geometric mean steady-state concentrations of (R)-bicalutamide, the departures from linearity were 4%, 13%, 17%, and 32% with dosages of 100, 150, 200, and 300 mg/day, respectively. There is a plateau in steady-state levels of (R)-bicalutamide with bicalutamide dosages above 300 mg/day, and, accordingly, dosages of bicalutamide of 300 to 600 mg/day result in similar circulating concentrations of (R)-bicalutamide and similar degrees clinically of efficacy, tolerability, and toxicity. Relative to 150 mg/day bicalutamide, levels of (R)-bicalutamide are about 15% higher at a dosage of 200 mg/day and about 50% higher at a dosage of 300 mg/day. In contrast to (R)-bicalutamide, the inactive enantiomer (S)-bicalutamide is much more rapidly absorbed (as well as cleared from circulation).
|50 mg||150 mg|
|tmax||31 hours||39 hours|
|tss||4–12 weeks||4–12 weeks|
Steady-state concentrations of the drug are reached after 4 to 12 weeks of administration independently of dosage, with an approximate 10- to 20-fold progressive accumulation of circulating levels of (R)-bicalutamide. In spite of the relatively long time to reach steady-state (which is a product of its long elimination half-life), there is evidence that the achieved AR blockade of bicalutamide is equivalent to that of flutamide by the end of the first day of treatment. With single 50 mg and 150 mg doses of bicalutamide, mean peak concentrations (Cmax) of (R)-bicalutamide are 0.77 μg/mL (1.8 μmol/L) (at 31 hours) and 1.4 μg/mL (3.3 μmol/L) (at 39 hours), respectively. At steady-state, mean circulating concentrations (Css) of (R)-bicalutamide with 50 mg/day and 150 mg/day bicalutamide are 8.9 μg/mL (21 μmol/L) and 22 μg/mL (51 μmol/L), respectively. In another 150 mg/day bicalutamide study, mean circulating concentrations of (R)-bicalutamide were 19.4 μg/mL (45.1 μmol/L) and 28.5 μg/mL (66.3 μmol/L) on days 28 and 84 (weeks 4 and 12) of treatment, respectively.
The tissue distribution of bicalutamide is not well-characterized. However, it has been reported that distribution studies with bicalutamide have shown that preferential (i.e., tissue-selective) accumulation in anabolic (e.g., muscle) tissues does not occur. There are no available data on hepatic bicalutamide concentrations in humans, but a rat study found that oral bicalutamide treatment resulted in 4-fold higher concentrations of the drug in the liver relative to plasma (a common finding with orally administered drugs, due to transfer through the hepatic portal system prior to reaching circulation). In men receiving 150 mg/day bicalutamide, concentrations of (R)-bicalutamide in semen were 4.9 μg/mL (11 μmol/L), and the amount of the drug that could potentially be delivered to a female partner during sexual intercourse is regarded as low (estimated at 0.3 μg/kg) and below the amount that is required to induce changes in the offspring of laboratory animals. Bicalutamide is highly protein-bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide), mainly to albumin. It has negligible affinity for SHBG and no affinity for corticosteroid-binding globulin.
Based on animal research, it was initially thought that bicalutamide was unable to cross the blood–brain barrier into the central nervous system and hence would be a peripherally-selective antiandrogen in humans. This conclusion was drawn from the finding that bicalutamide does not increase LH or testosterone levels in multiple tested animal species (including rats and dogs), as antiandrogens like flutamide normally do this by blocking ARs in the pituitary gland and hypothalamus in the brain and thereby disinhibiting the HPG axis. In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparable extent relative to flutamide and nilutamide. As such, it appears that there are species differences in the central penetration of bicalutamide and that the drug does indeed cross the blood–brain barrier and affect central function in humans, as supported by potential side effects, in spite of increased testosterone levels, like hot flashes and diminished sexual interest in men. A newer NSAA, darolutamide, has been found to negligibly cross the blood–brain barrier in both animals and humans, and in accordance, unlike bicalutamide, does not increase LH or testosterone levels in humans.
The metabolism of bicalutamide is hepatic and stereoselective, the inactive (S)-enantiomer is metabolized mainly by glucuronidation and is rapidly cleared from circulation, while the active (R)-isomer is slowly hydroxylated and then glucuronidated. In accordance, the active (R)-enantiomer has a far longer elimination half-life than the (S)-isomer, and circulating levels of (R)-bicalutamide are 10- to 20-fold and 100-fold higher than those of (S)-bicalutamide after a single dose and at steady-state, respectively. (R)-Bicalutamide is almost exclusively metabolized via hydroxylation into (R)-hydroxybicalutamide by the cytochrome P450 enzyme CYP3A4. Bicalutamide is also glucuronidated by UGT1A9, a UDP-glucuronyltransferase, into bicalutamide glucuronide, and (R)-hydroxybicalutamide glucuronide is formed from the metabolism of (R)-hydroxybicalutamide by UGT1A9. Similar to the inactive (S)-enantiomer of bicalutamide, (R)-hydroxybicalutamide is glucuronidated and rapidly cleared from circulation. None of the metabolites of bicalutamide are known to be active. Following administration of bicalutamide, only low concentrations of the metabolites are detectable in blood plasma, while unchanged bicalutamide predominates. (R)-Bicalutamide has a long elimination half-life of 5.8 days with a single dose, and an elimination half-life of 7–10 days with repeated administration, which allows for convenient once-daily dosing of bicalutamide.
Bicalutamide is eliminated in feces (43%) and urine (34%), whereas its metabolites are eliminated in approximately equal proportions in urine and bile. It is excreted to a substantial extent in its unmetabolized form, with both bicalutamide and its metabolites excreted mainly as glucuronide conjugates.
Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory). Its systematic name (IUPAC) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide. The compound has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.373 g/mol, and is a fine white to off-white powder.
The acid dissociation constant (pKa') of bicalutamide is approximately 12, it is a highly lipophilic compound (log P = 2.92). At 37 °C (98.6 °F), or normal human body temperature, bicalutamide is practically insoluble in water (4.6 mg/L), acid (4.6 mg/L at pH 1), and alkali (3.7 mg/L at pH 8). In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.
Structure and analogues
First-generation NSAAs including bicalutamide, flutamide, and nilutamide are synthetic, nonsteroidal anilide (N-phenyl amide) derivatives and structural analogues of each other. Bicalutamide is a diaryl propionamide, while flutamide is a monoarylpropionamide and nilutamide is a hydantoin. Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides. All three of the compounds share a common 3-trifluoromethyl aniline moiety. Bicalutamide is a modification of flutamide in which a 4-fluoro phenyl sulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group. Topilutamide, also known as fluridil, is another NSAA that is closely related structurally to the first-generation NSAAs, but, in contrast to them, is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of androgenic alopecia.
The second-generation NSAAs enzalutamide and apalutamide were derived from and are analogues of the first-generation NSAAs, while another second-generation NSAA, darolutamide, is said to be structurally distinct and chemically unrelated to the other NSAAs. Enzalutamide is a modification of bicalutamide in which the inter-ring linking chain has been altered and cyclized into a 5,5-dimethyl-4-oxo-2-thioxo imidazolidine moiety. In apalutamide, the 5,5-dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessory cyclobutane ring and one of its phenyl rings is replaced with a pyridine ring.
In 1998, researchers discovered the first nonsteroidal androgens (the arylpropionamides) via structural modification of bicalutamide. Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs). Lead SARMs of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4). They are very close to bicalutamide structurally, with the key differences being that the linker sulfone of bicalutamide has been replaced with an ether or thioether group to confer agonism of the AR and the 4-fluoro atom of the pertinent phenyl ring has been substituted with an acetamido or cyano group to eliminate reactivity at the position.
Radiotracers for medical imaging
A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging, they include [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide, the latter two were found to have substantially increased affinity for the AR relative to that of bicautamide. However, none of these agents have been evaluated in humans.
5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the AR and has approximately 150-fold higher affinity for the AR and about 20-fold greater functional inhibition of the AR relative to bicalutamide. It is among the most potent AR antagonists ever to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.
A number of chemical syntheses of bicalutamide have been published in the literature. The procedure of the first published chemical synthesis of bicalutamide (Tucker et al., 1988) can be seen below.
Bicalutamide as well as all of the other currently marketed NSAAs were derived from structural modification of flutamide, which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity. Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries in the 1980s and was selected for development from a group of over 1,000 synthesized compounds. It was first patented in 1982 and was first reported in the scientific literature in June 1987.
Bicalutamide was first studied in a phase I clinical trial in 1987 and the results of the first phase II clinical trial in prostate cancer were published in 1990. The pharmaceutical division of ICI was split out into an independent company called Zeneca in 1993, and in April and May 1995, Zeneca (now AstraZeneca, after merging with Astra AB in 1999) began pre-approval marketing of bicalutamide for the treatment of prostate cancer in the U.S.. It was first launched in the U.K. in May 1995, and was subsequently approved by the U.S. FDA on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a GnRH analogue.
Following its introduction for use in combination with a GnRH analogue, bicalutamide was developed as a monotherapy at a dosage of 150 mg/day for the treatment of prostate cancer, and was approved for this indication in Europe, Canada, and a number of other countries in the early 2000s. This application of bicalutamide was also under review by the FDA in the U.S. in 2002, but ultimately was not approved in this country. In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a GnRH analogue for prostate cancer. The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men.
Subsequent to negative findings of bicalutamide monotherapy for LPC in the EPC trial, approval of bicalutamide for use specifically in the treatment of LPC was withdrawn in a number of countries including the U.K. (in October or November 2003) and several other European countries and Canada (in August 2003). In addition, the U.S. and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication. The drug is effective for, remains approved for, and continues to be used in the treatment of LAPC and mPC, on the other hand.
Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the SAA CPA in 1973 and the NSAAs flutamide in 1983 (1989 in the U.S.) and nilutamide in 1989 (1996 in the U.S.). It has been followed by abiraterone acetate in 2011 and enzalutamide in 2012, and may also be followed by in-development drugs such as apalutamide, darolutamide, and seviteronel.
Society and culture
Bicalutamide is the generic name of the drug in English and French and its INN, USAN, USP, BAN, DCF, AAN, and JAN. It is also referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages. The "-lutamide" suffix corresponds to that for NSAAs. Bicalutamide is also known by its former developmental code name ICI-176,334.
Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries. It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries, the drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well. A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.
Bicalutamide is a prescription drug, it is not specifically a controlled substance in any country and therefore is not an illegal drug. However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.
Bicalutamide is off-patent and available as a generic, and its cost is very low in comparison to a number of other similar medications (from US$10 to US$15.44 for a 30-day supply of once-daily 50 mg tablets). Brand name Casodex costs US$556.17 for a 30-day supply of once-daily 50 mg tablets as of 2017[update]. Unlike bicalutamide, the newer NSAA enzalutamide is still on-patent, and for this reason, is far more expensive in comparison (US$7,450 for a 30-day supply as of 2015[update]).
The patent protection of all three of the first-generation NSAAs has expired and flutamide and bicalutamide are both available as relatively inexpensive generics. Nilutamide, on the other hand, has always been a poor third competitor to flutamide and bicalutamide and, in relation to this fact, has not been developed as a generic and is only available as brand name Nilandron, at least in the U.S.
Bicalutamide is far less expensive than GnRH analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost US$10,000–$15,000 per year (or about US$1,000 per month) of treatment.
Sales and usage
|Total sales: $13.0 billion (as of end 2016)|
|* First generic availability|
Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007, and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007. In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca. Total worldwide sales of brand name Casodex were approximately US$13.0 billion as of the end of 2016.
Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions of bicalutamide were dispensed in the U.S., or about 400,000 prescriptions per year. During that time, bicalutamide accounted for about 87.2% of the NSAA market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it. Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm. About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).
A phase II clinical trial of bicalutamide with everolimus in mCRPC has been conducted. Bicalutamide has also been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.
Benign prostatic hyperplasia
Bicalutamide has been studied in the treatment of benign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day. Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased. Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo, the decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitor finasteride, which is approved for the treatment of BPH. Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.
AR-positive breast cancer
Bicalutamide has been tested for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study for this indication. Enzalutamide is also being investigated for this type of cancer.
Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets. However, it has not been formally assessed in controlled studies for this purpose.
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RBA (%): R-bicalutamide: 0.4%; Flutamide: 0.01%; Hydroxyflutamide: 0.1%; Nilutamide: 0.08%
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The only advantage of cyproterone acetate on pure antiandrogens seems to be the low incidence of hot flushes; [...] However, hepatotoxicity associated with long term daily doses of 300 mg daily and the unacceptably high incidence of cardiovascular side effects (10%) should restrict its use to patients who are intolerant of pure antiandrogen compound. In contrast to steroidal compound nonsteroidal compounds let sexual potency to be retained, [...]
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