The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
Prostate cancer 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 gonadotropin-releasing hormone analogue (GnRH analogue) or orchiectomy (that is, surgical or medical castration) in the treatment of stage D2 metastatic prostate cancer (mPC), and as a monotherapy at a dosage of 150 mg/day for the treatment of stage C or D1 locally advanced prostate cancer (LAPC). Although effective in and , bicalutamide is no longer indicated for the treatment of localized prostate cancer (LPC) due to negative findings in the Early Prostate Cancer (EPC) clinical trial programme. Prior to the introduction of the newer 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 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.
In the early 1940s, it was discovered that growth of prostate cancer in men regressed with surgical castration or high-dose estrogen therapy, which produced very low levels of circulating testosterone, and accelerated with the administration of exogenous testosterone. It has since been elucidated that androgens like testosterone and dihydrotestosterone (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, , analogues, , and androgen biosynthesis inhibitors (e.g., abiraterone acetate), has become the mainstay of treatment for prostate cancer. Although can shrink or stabilize prostate tumors and hence significantly slow the course of prostate cancer and prolong life, it is not generally curative. While effective in slowing the progression of the disease initially, most advanced prostate cancer patients eventually become resistant to and prostate cancer growth starts to accelerate again, in part due to progressive mutations in the androgen receptor (AR) that result in the transformation of drugs like bicalutamide from antagonists to agonists.
A few observations form the basis of the reasoning behind combined androgen blockade (CAB), in which castration and an 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 , 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 . 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 with 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 than those used in is roughly equivalent to castration in extending life in men with prostate cancer. Moreover, 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 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, monotherapy has become an important alternative to castration and in the treatment of prostate cancer.
Bicalutamide may be used to reduce the effects of the testosterone flare at the initiation of agonist therapy.
The combination of bicalutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of and as an alternative to the combination of bicalutamide with surgical or medical castration.
Skin and hair conditions
Androgens like testosterone and 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 polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (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 medication was well tolerated, all of the patients experienced a visible increase 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 (from 22.0 ± 5.1 to 8.6 ± 3.5). According to a 2013 review, "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to and . It does not have any significant side effects [or lead] to irregular periods." In 2017, the combination of bicalutamide with a combined birth control pill was evaluated in a phase III clinical trial for the treatment of severe hirsutism in women with , and was found to be significantly more effective than a combined birth control pill alone. In addition, bicalutamide was shown to be safe and to produce no side effects, except for a significant increase in total cholesterol and low-density lipoprotein levels. Studies have reported bicalutamide to be effective in the treatment of scalp hair loss in women.
In addition to hirsutism, bicalutamide can be used in the treatment of acne in women. Flutamide has generally been found to reduce symptoms of acne by 80 or 90% even at low doses, with several studies showing complete acne clearance. In one study, it decreased acne scores by 80% within 3 months, whereas the spironolactone decreased symptoms by only 40% in the same time period. Bicalutamide has an antiandrogenic efficacy that is comparable to or greater than that of flutamide, and would be expected to produce similar therapeutic benefits. Other androgen-dependent skin and hair conditions, such as seborrhea and pattern hair loss, may also be treated by bicalutamide. In addition to acne, flutamide has been found to produce an 80% or greater decrease in scores of seborrhea and androgen-dependent scalp hair loss. Moreover, in combination with a combined birth control pill, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in almost all women suffering from pattern hair loss in one small study. Bicalutamide is an appealing alternative to flutamide for the treatment of androgen-dependent skin and hair conditions in women because flutamide has a considerable risk of serious liver toxicity, which bicalutamide does not share.
Antiandrogens like flutamide and bicalutamide are male-specific teratogens which can feminize male fetuses due to their antiandrogen effects. For this reason, they are not recommended by the Food and Drug Administration 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. Birth control pills, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, birth control pills themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions; hence, they can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.
Transgender hormone therapy
Bicalutamide is used as an antiandrogen in feminizing hormone therapy for transgender women and as a puberty blocker in adolescent transgender girls. It can be used in transgender females both in combination with an estrogen and alone. The medication directly blocks the effects of androgens like testosterone and dihydrotestosterone in the body, and, when used by itself, also induces a significant increase in estradiol levels. As a result, bicalutamide causes demasculinization, and can additionally promote feminization, even without concomitant use of estrogen. This is analogous to what occurs in women with a defective due to complete androgen insensitivity syndrome. Demasculinizing and feminizing effects of bicalutamide in those assigned male at birth include breast development, reduced male-pattern hair, decreased muscle mass, feminine changes in fat distribution, decreased sex drive, and reduced spontaneous erections. Dosages of bicalutamide of 25 to 50mg/day have been used and recommended in transgender females. Lower doses may also be effective.