Side effects of bicalutamide

Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer.[14]

The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.[15] These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,[16] but gynecomastia is generally reported to occur in 70 to 80% of patients.[17] 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.[18][19] Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment.[14] In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity.[19][20] 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.[21] In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.[19] 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.[20] The incidence and severity of gynecomastia are reportedly higher with estrogens (e.g., diethylstilbestrol) than with NSAAs like bicalutamide in the treatment of men with prostate cancer.[22]

Management

Severe gynecomastia in a 64-year-old man treated with 150 mg/day bicalutamide for prostate cancer. Before (A) and after (B) surgical breast reduction.[23]

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.[24][25] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.[24][25] 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.[24][25] 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.[26] Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.[27]

Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men

Time	Placebo	1 mg/day	2.5 mg/day	5 mg/day	10 mg/day	20 mg/day
6 months	98%	90%	80%	54%	22%	10%
12 months	99%	95%	84%	56%	38%	19%
Notes: Prevention of bicalutamide-induced breast symptoms with tamoxifen in men. Breast symptoms were specifically gynecomastia and breast pain. Sources: [28][29]

Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction.[18] However, the rates of these side effects with bicalutamide monotherapy are very low.[18] 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.[18] 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.[19] About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age,[30] maintained sexual interest, while sexual function was slightly reduced by 18%.[19] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs.[15] Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.[31][32]

Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women.[33] 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.[33] Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide.[34][35] 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,[36] as well as 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.[36] It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.[37]

Bicalutamide reduces the size of the prostate gland and seminal vesicles,[38] though not of the testes.[39] Significantly reduced penile length is also a recognized adverse effect of ADT.[40][41] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur.[42][43] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men.[39][44] 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),[45] but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.[46][44][47]

The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively).[19] 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.[48]

In the EPC trial, 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.[18] 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).[18][19]

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.[49]

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.[50] In accordance, anabolic–androgenic steroids (AAS) such as oxymetholone and nandrolone decanoate are approved and used in the treatment of severe anemia,[50][51] and AAS can cause polycythemia as an adverse effect in high dosages.[50] Conversely, whether via castration, NSAA monotherapy, or CAB, mild anemia is a common side effect of ADT in men.[46][52] The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials.[46] A decrease of hemoglobin levels of 1–2 g/dL after approximately six months of treatment may be observed.[52]

Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes.[46] 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.[46]

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,[53] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,[54] occur much more frequently in combination with a GnRH analogue.[31][55][56] It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogens may compensate for various negative central effects of androgen deprivation.[31] 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.[53] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.[57]

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%).[49][58][59] 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).[49][59][18] 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.[18][60] In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated,[17] it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation.[61] 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).[62]

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:[63]

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.[63]

A study of 300 to 600 mg/day bicalutamide monotherapy in 248 men with LAPC or metastatic prostate cancer found that there were no effects of bicalutamide on heart rate, blood pressure, or electrocardiogram parameters.[64][65] In addition, at 5-year follow-up, the incidence of cardiovascular events was low, with no differences between the bicalutamide and castration groups.[64][65] There were also no differences in the incidences of arrhythmia, myocardial infarction, or other ischemic cardiac or cerebrovascular conditions.[64][65] These findings suggest that bicalutamide does not cause an excess in cardiovascular events or conditions.[64][65]

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.[66] Non-prostate cancer mortality was not specifically assessed.[66]

A case report in which bicalutamide was described as a probable cause of heart failure in an elderly man with prostate cancer has been published.[67]

As a result of androgen deprivation therapy, bicalutamide may increase the risk of kidney failure in men.[68]

Bicalutamide may cause liver changes rarely, such as elevated transaminases and jaundice.[69] 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.[18][70] For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide,[69][71] and (dose-dependently) between 10% and 28% for CPA,[72][73][74] whereas there appears to be no risk with enzalutamide.[75][76] In the EPC trial, bicalutamide-induced liver changes were usually transient and rarely severe.[18] The medication 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.[77][78]

The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.[18][79] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.[80] 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.[77] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.[77]

A total of 7 case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature as of 2018.[81][69][82] One of these cases occurred after two doses of bicalutamide, and has been said to more likely to have been caused by prolonged prior exposure of the patient to flutamide and CPA.[69][71][83][84][85] In the reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50 mg/day (three), 80 mg/day (one), 100 mg/day (one), and 150 mg/day (two).[81][82] Relative to flutamide (which has an estimated incidence rate of 0.03% or 3 per 10,000), hepatotoxicity is far rarer with bicalutamide and nilutamide, and bicalutamide is regarded as having the lowest risk of the three medications.[86][83][87] For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.[72] 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.[72]

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.[18][70][69][82] It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity.[88][89] As such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women.[88][89] However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.[90]

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.[91] 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.[92][93][94][95] 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.[83][92][95][96]

Several case reports of interstitial pneumonitis (which can progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature.[98][99][100][101] Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,[102] and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).[103]^:81[99][104] 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% (4 per 10,000) for flutamide and 0.01% (1 per 10,000) for bicalutamide.[3] 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.[105] 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.[106][107] 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).[108]

A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported.[109][110][111] 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.[109] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.[109][111]

A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published.[112] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."[112] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.[112][113] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,[114] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),[30][115] and millions of men have been treated with bicalutamide for prostate cancer,[116] all of which are potentially in support of the notion of chance co-occurrences.[112] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."[112]

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.[117][118][119][120] 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.[77] 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.[77] As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.[117][118]