The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.
In men with prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death due to causes other than prostate cancer. Bicalutamide has been found to cause unfavorable liver changes in around 3 to 11% of people, with such changes necessitating discontinuation in approximately 1%. Rarely, bicalutamide has been associated with serious liver toxicity and lung disease, as well as sensitivity to light. It has also uncommonly been associated with hypersensitivity reactions. Bicalutamide has a theoretical risk of birth defects in male fetuses.
Central nervous system.
Hot flashes.
In the Early Prostate Cancer (EPC) clinical trial programme, at 7.4 years follow-up, the rate of hot flashes was 9.2% for bicalutamide monotherapy 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 monotherapy was 13.1% (relative to 50.0% for castration).
Sexual dysfunction.
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. Similarly, in the trials of 150 mg/day bicalutamide monotherapy for advanced prostate cancer, fewer than 10% of men reported decreased sex drive or reduced erectile function as a side effect. About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age, maintained sexual interest, while sexual function was slightly reduced by 18%. Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs. Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer. The preservation of sexual desire and function with NSAA monotherapy may be related to testosterone metabolites such as estradiol and the 3α-androstanediol maintaining these functions rather than the androgen receptor or to bicalutamide and other NSAAs possibly incompletely blocking the androgen receptor in the brain.
Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women. A phase III clinical study of 50 mg/day bicalutamide in conjunction with a combined oral contraceptive in women with severe hirsutism due to polycystic ovary syndrome (PCOS) carefully assessed the side effect of decreased libido and found that the incidence with bicalutamide did not differ from the control group. Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide. These findings are in accordance with the fact that women with complete androgen insensitivity syndrome (CAIS) show normal sexual function in spite of complete loss of androgen receptor (AR) signaling. They are also in accordance with a variety of findings concerning testosterone levels and sexual function in premenopausal women, in which no change in parameters of sexual function, including libido, have been observed in association with increases or decreases in testosterone levels. It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.
Psychiatric conditions.
At 5.3 years follow-up, the incidence of depression was 5.5% for bicalutamide monotherapy relative to 3.0% for placebo in the EPC trial, and the incidence of asthenia (weakness or fatigue) was 10.2% for bicalutamide monotherapy relative to 5.1% for placebo. Rarely, bicalutamide has been associated with hallucinations. This is thought to be secondary to AR antagonism.
Breasts and reproductive system.
Breast changes.
The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia. These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy, but gynecomastia is generally reported to occur in 70 to 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.
Rates of gynecomastia with bicalutamide monotherapy and monotherapy with other NSAA varies significantly across different trials, in reviews ranging from 38 to 85% with bicalutamide, 21 to 80% with flutamide, and 50 to 79% with nilutamide. This variation is presumably related to factors like duration of therapy, differing patient characteristics, and the specific methods of collection of adverse-event data. One review noted that rates of breast side effects were much lower with open questioning (23–26% for gynecomastia and 26–31% for breast tenderness at 50–150mg/day bicalutamide) as opposed to direct questioning in studies of bicalutamide monotherapy for prostate cancer.
Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment. In one study, 89% of those who developed gynecomastia and 98% of those who developed breast pain did so within the first 6months. Of those who developed gynecomastia, around 55% did so in the first 3months, around 35% between 3 and 6months, and 10% after more than 6months. For breast pain, rates were around 75% in the first 3months, 25% between 3 and 6months, and less than 5% after more than 6months. In the EPC programme, 85% who developed breast pain did so in the first 6months and 80% who developed gynecomastia did so in the first 9months.
In more than 90% of affected men, bicalutamide-related breast changes 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 addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy. 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. Gynecomastia and breast pain improved or resolved upon discontinuation in 70 and 90% of patients, respectively. Resolution of breast symptoms was dependent on duration of bicalutamide therapy, with resolution rates ranging from 29% with ;18months of treatment to 64% for ;6months of treatment.
Gynecomastia and breast pain/tenderness with NSAA monotherapy is due to increased estradiol levels and unopposed estrogen action in the breasts due to androgen receptor blockade (as androgens inhibit the effects of estrogens in the breasts).
The incidence and severity of gynecomastia are reportedly slightly higher with estrogens (e.g., diethylstilbestrol) (40–80%) than with NSAAs like bicalutamide (40–70%) in the treatment of men with prostate cancer.
Management of breast changes.
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 2015 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. A 2019 network meta-analysis likewise concluded that tamoxifen was more effective than radiotherapy or anastrozole for preventing bicalutamide-induced gynecomastia. Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.
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."
Lower reproductive system.
Bicalutamide reduces the size of the prostate gland and seminal vesicles, though not of the testes. Slightly but 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. 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 clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.
Male birth defects.
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. Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.
Skin, fat, and bone.
Skin changes.
Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects in the skin and on hair follicle distribution in people assigned male at birth. 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.
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). Eventually, the symptoms disappeared and did not recur. Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.
Fat distribution.
Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects on fat distribution in people assigned male at birth.
Bone density and fractures.
Bicalutamide monotherapy preserves bone mineral density in men with prostate cancer relative to surgical or medical castration. This is considered to be due to preservation of gonadal estradiol production with bicalutamide monotherapy, in contrast to castration which greatly reduces estradiol levels. The risk of osteoporosis and serious bone fractures with bicalutamide monotherapy appears to be no different than with non-use in men with prostate cancer.
Gastrointestinal system.
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.
Heart, liver, kidneys, and lungs.
Cardiovascular system.
A study of high-dose bicalutamide monotherapy (300–600mg/day) in 248men with LAPC or metastatic prostate cancer found that there were no effects of bicalutamide on heart rate, blood pressure, or electrocardiogram parameters. At the 5-year follow-up of the study, the incidence of cardiovascular events was low, with no differences between the bicalutamide group and the castration group. There were also no