^ abMay occur as often as 90% of those taking bicalutamide, but is mild-to-moderate in 90% of occurrences. Incidence greatly decreased in combination with castration.
^Usually transient, rarely severe. Resolves or improves with continued therapy or on discontinuation.
^ abReported in single cases, but not observed in any large, randomized trial. With regular liver monitoring and discontinuation as needed.
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.[8] 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).[8][9]
Sexual dysfunction
Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction.[8] However, the rates of these side effects with bicalutamide monotherapy are very low.[8] 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.[8] 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.[9] About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age,[10] maintained sexual interest, while sexual function was slightly reduced by 18%.[9] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs.[11] Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.[12][13] 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.[14][15]
Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women.[16] A phase IIIclinical 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.[16] Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide.[17][18] 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.[19] 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.[19] It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.[20]
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.[21] Rarely, bicalutamide has been associated with hallucinations.[22] This is thought to be secondary to AR antagonism.[22]
Footnotes:a = Testosterone levels increased to ~460–610 ng/dL and estradiol levels to ~32–51 pg/mL. b = Testosterone levels increased to ~505–715 ng/dL and estradiol levels to ~32–53 pg/mL. c = Testosterone levels increased to ~540–600 ng/dL and estradiol levels to ~29–34 pg/mL.
Breast changes
Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer.[28]
The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.[11] These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,[29] but gynecomastia is generally reported to occur in 70 to 80% of patients.[30] 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.[8][9]
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.[31][32] This variation is presumably related to factors like duration of therapy, differing patient characteristics, and the specific methods of collection of adverse-event data.[32][23] 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.[23]
Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment.[28][33][34] In one study, 89% of those who developed gynecomastia and 98% of those who developed breast pain did so within the first 6months.[33] 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.[33] For breast pain, rates were around 75% in the first 3months, 25% between 3 and 6months, and less than 5% after more than 6months.[33] 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.[34]
In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity.[9][35][34] 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.[36] In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.[9] 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.[35][34] Gynecomastia and breast pain improved or resolved upon discontinuation in 70 and 90% of patients, respectively.[34] 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.[34]
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).[32]
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.[37][31]
Management of breast changes
Severe gynecomastia with 150 mg/day bicalutamide monotherapy in a 64-year-old man with prostate cancer. Before (left) and after (right) surgical breast reduction.[38]
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.[39][40] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.[39][40] 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.[39][40] 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.[41] A 2019 network meta-analysis likewise concluded that tamoxifen was more effective than radiotherapy or anastrozole for preventing bicalutamide-induced gynecomastia.[42]Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.[31]
Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up timepoint
Tamoxifen dosage
Placebo
1 mg/day
2.5 mg/day
5 mg/day
10 mg/day
20 mg/day
0 months
–
6 months
98%
90%
80%
54%
22%
10%
12 months
99%
95%
84%
56%
38%
19%
Notes: Prevention of breast symptoms—specifically gynecomastia and breast pain—induced by 150 mg/day bicalutamide monotherapy with tamoxifen in 282 men with prostate cancer. Bicalutamide and tamoxifen were initiated at the same time (0 months). Estradiol levels were in the range of about 22 to 47 pg/mL in the treated group.[43]Sources:[44][43]
Male breast cancer
A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published.[45] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."[45] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.[45][46] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,[47] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),[10][48] and millions of men have been treated with bicalutamide for prostate cancer,[49] all of which are potentially in support of the notion of chance co-occurrences.[45] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."[45]
Lower reproductive system
Bicalutamide reduces the size of the prostate gland and seminal vesicles,[50] though not of the testes.[51] Slightly but significantly reduced penile length is also a recognized adverse effect of ADT.[52][53] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur.[54][55] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men.[51][56] 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),[57] but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.[58][56][59]
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.[60][61][62][63] 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.[64] 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.[64] As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.[60][61] Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.[65]
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.[66] Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes.[58] 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.[58]
Sensitivity to light
A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported.[67][68][69] 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.[67] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.[67][69]
Bicalutamide monotherapy preserves bone mineral density in men with prostate cancer relative to surgical or medical castration.[7][70][71][72][73] This is considered to be due to preservation of gonadal estradiol production with bicalutamide monotherapy, in contrast to castration which greatly reduces estradiol levels.[7] 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.[74]
Gastrointestinal system
The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively).[9] 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.[75]
In the LPC group of the EPC study, which compared 150mg/day bicalutamide monotherapy versus placebo/standard care, there were numerically more deaths from heart failure (1.2% vs. 0.6%; 49 vs. 25 patients) in the bicalutamide group.[8][78] This contributed to a trend toward significantly increased mortality due to causes other than prostate cancer in the bicalutamide group.[21][79][80]Cardiovascularmorbidity, on the other hand, was similar between the bicalutamide and placebo groups.[8][78] In the NRG/RTOG 9601 trial, bicalutamide monotherapy significantly increased the risk of grade 3 to 5 cardiovascular incidents after a median 13years of follow-up.[81]
A systematic review and meta-analysis of randomized controlled trials of ADT and risk of cardiovascular death in men with non-metastatic prostate cancer was published in 2011.[82] It assessed ADT in the form of a GnRH agonist or surgical castration alone or in combination with a NSAA and included over 4,000patients.[82] The meta-analysis found no evidence of increased cardiovascular mortality or overall mortality.[82] Non-prostate cancer mortality was not specifically assessed.[82] A limitation of the meta-analysis was that of the trials included in the meta-analysis, only flutamide was employed and not bicalutamide.[82] Subsequent reviews and meta-analyses, published between 2014 and 2022, have reported positive though inconsistent associations of ADT with cardiovascular complications and death.[83][84][85][86][87][88][89]
A case report in which bicalutamide was described as a probable cause of heart failure in a man with prostate cancer has been published.[90]
Androgens including testosterone are known to stimulate erythropoiesis (formation of red blood cells) and increase hematocrit (red blood cell levels).[121][122][123] These effects are mediated by increasing production and secretion of erythropoietin from the kidneys.[122] Erythropoietin in turn stimulates erythropoiesis in hematopoietictissues such as bone marrow.[124] The high levels of testosterone in males are why hematocrit and hemoglobin levels are higher in men than in women.[125] Due to stimulation of erythropoiesis, anabolic–androgenic steroids (AAS) such as oxymetholone and nandrolone decanoate are effective for and used in the treatment of severe anemia (very low hematocrit).[122][126] High doses or levels of AAS, including testosterone, can cause polycythemia—high red blood cell and/or hemoglobin levels that increase the risk of stroke—as an adverse effect.[121][122] Conversely, whether via castration, NSAA monotherapy, or CAB, decreased erythropoiesis resulting in mild anemia is a common side effect of ADT in men.[58][127][123] The incidence of anemia with bicalutamide either as a monotherapy or with castration was about 7.3 to 7.5% in clinical trials, which was similar to the rate with castration of about 7.1%.[58][123] A decrease of hemoglobin levels of 1 to 2 g/dL after about 6months of treatment may be observed.[127]
Bicalutamide can cause adverse liver changes rarely, such as elevated transaminases, jaundice, hepatitis, and liver failure.[130] In the EPC trial, in which bicalutamide monotherapy (150 mg/day) was evaluated for treatment of early prostate cancer in 8,113men, the incidence of abnormal liver function tests at 3-year median follow-up was 3.4% for bicalutamide plus standard care (n=4,052) and 1.9% for standard care alone (n=4,061).[8][131] However, in a phase 3 clinical trial of bicalutamide (50 mg/day) plus a GnRH agonist versus flutamide (750 mg/day) plus a GnRH agonist for metastatic prostate cancer, the rate of abnormal liver function tests was 7.5% with bicalutamide (n=401) and 11.3% with flutamide (n=407).[132][133][134][123][58] Markedly elevated liver enzymes occurred at rates of 0.5% with bicalutamide and 2.5% with flutamide in this trial, whereas rates of drug discontinuation due to elevated liver enzymes were 1.5% with bicalutamide and 2.0% with flutamide.[58][135] In clinical trials, bicalutamide-induced liver changes have usually been transient and have rarely been severe.[8][58] Bicalutamide was discontinued due to liver changes (manifested as hepatitis or marked increases in liver enzymes) in clinical trials in 0.3% to 1.5% of patients, or approximately 1% overall.[64][8][136][137][135] Aside from men with prostate cancer, liver changes have also been observed in women treated with low doses of bicalutamide (10–50mg/day) for scalp hair loss.[138] Rates of elevated liver enzymes have ranged from 2.9 to 11.4% in these studies, which spontaneously resolved in some women and necessitated discontinuation of treatment in others.[138][139]
No cases of liver failure or death due to liver toxicity were seen with bicalutamide in the initial clinical development programme for prostate cancer which included over 3,900men treated with bicalutamide.[58][134][140][141][114] These trials employed bicalutamide alone (as a monotherapy) and in combination with castration at doses ranging from 10 to 450mg/day (with most patients receiving 50 to 150mg/day).[134][58] Fivecases of jaundice, including one man who died of prostate cancer, chronic renal failure, and jaundice, were recorded in the programme.[58][140][141] Rates of jaundice with bicalutamide in the programme were similar to comparator therapies.[58] No instances of fatal hepatotoxicity occurred with 150mg/day bicalutamide monotherapy in the SPCG-6Tooltip Scandinavian Prostate Cancer Group 6 substudy of the EPC programme, in which 607men received bicalutamide.[21] Following the initial clinical development programme of bicalutamide for prostate cancer and the EPC programme, cases of grade 3 to 4 (severe or life-threatening/disabling) adverse liver changes have been reported with bicalutamide in subsequent individual trials of bicalutamide for treatment of various types of cancer.[142][143][144][145]
The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.[8][146] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.[147] Liver changes with bicalutamide usually occur within the first 3 to 6 months of treatment, and it is recommended that liver function be monitored regularly for the first 4 months of treatment and periodically thereafter.[64][58] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.[64]
As of 2022, at least 10 case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature.[148][149][130][150][112][151] The dosages of bicalutamide in the cases ranged from 50 to 150 mg/day and the onsets were all within 6 months of therapy.[149][130][150][112][151] One of the cases onset after only two doses of bicalutamide and may have been more related to prolonged prior exposure to flutamide and CPA.[130][152] Aside from published case reports, hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database.[153] Similarly, additional cases exist in and have been described in published research for other pharmacovigilance systems, such as the Spanish pharmacovigilance system.[154]
Liver toxicity is considered to be much more rare with bicalutamide than with flutamide, and bicalutamide is also regarded as having a lower risk than nilutamide.[155][156][157] Rates of abnormal liver function tests have varied widely between studies, with reported ranges of 4 to 62% with flutamide and 2 to 33% with nilutamide.[123][158][159] The risk of serious or fatal liver toxicity with flutamide has been estimated to be 3 in 10,000cases, and other studies suggest an even higher incidence.[32][158] By 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.[160] 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.[160] The review also cited a report of an additional 96 instances of hepatotoxicity that were attributed to CPA, of which 33 resulted in death.[160] However, clinically significant liver toxicity has almost exclusively been associated with high doses of CPA in men with prostate cancer (≥100 mg/day).[161][162][163]
There is no evidence of greater liver function changes with higher doses of bicalutamide, and hence the liver toxicity of bicalutamide is not currently known to be dose-dependent across its clinically used dosage range.[164] Older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity.[165][166] As such, the risk of liver changes with bicalutamide may be lower in younger individuals, for instance women with hirsutism and transgender women.[165][166] However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.[167]
Published case reports of bicalutamide-associated liver injury
#
Age
Sex
Dosage
Use
Onset
Outcome
Source
1
60 years
Male
50 mg/day
Prostate cancer
2 days
Survived
Dawson et al. (1997)
2
79 years
Male
80 mg/day
Prostate cancer
1.5 months
Survived
Ikemoto et al. (2000)
3
59 years
Male
50 mg/day
Prostate cancer
4 days
Death
O'Bryant et al. (2008)
4
61 years
Male
50 mg/day
Prostate cancer
3.5 months
Death
Castro Beza et al. (2008)
5
81 years
Male
150 mg/day
Prostate cancer
3 weeks
Survived
Hussain et al. (2014)
6
62 years
Male
100 mg/day
Prostate cancer
4.5 months
Survived
Yun et al. (2016)
7
67 years
Male
150 mg/day
Prostate cancer
3 weeks
Survived
Gretarsdottir et al. (2018)
8
79 years
Male
Unknown
Prostate cancer
15 days
Survived
Saito (2020)
9
17 years
Trans female
Unknown
Gender-affirming hormone therapy
1 year
Survived
Reed (2023)
10
17 years
Trans female
50 mg/day
Gender-affirming hormone therapy
3 months
Survived
Wilde et al. (2023)
Notes: Additional cases of bicalutamide-associated adverse liver changes have been reported. These include 11 cases in a 2006 Spanishpharmacovigilance system report (including 1 case of hepatitis, 2 cases of cholestatic hepatitis, 1 case of jaundice, 4 cases of elevated liver enzymes, and 1 case of elevated bilirubin; no deaths) and a number of cases in the FDA Adverse Event Reporting System (FAERS). Also 5 cases of jaundice were reported out of ~3,700 men in clinical trials but no cases of liver failure or of liver-toxicity-related death clearly attributable to bicalutamide were observed. Sources:Main:[177][178]
Lung toxicity
Case reports of interstitial pneumonitis associated with bicalutamide treatment have been published in the medical literature.[179][180][181][182] Hundreds of additional cases of interstitial lung disease in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database.[153] Interstitial pneumonitis can progress to pulmonary fibrosis and can be fatal. Interstitial pneumonitis with bicalutamide is said to be a very rare event.[183] The risk is much lower than that with nilutamide (which has an incidence rate of 0.5–2% of patients).[184]: 81 [180][185] In a large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was 0.77% for nilutamide, 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.[186] Strong safety signals of bicalutamide with interstitial lung disease have been observed in pharmacovigilance databases such as the FAERS and Japanese Adverse Drug Event Report (JADER) databases (e.g., RORTooltip reporting odds ratio = 9.2, 95% CITooltip confidence interval = 7.9–10.6; ROR = 8.2, 95% CI = 6.0–11.2).[187][188][189] Similar safety signals have been observed for certain other antiandrogens, like nilutamide and flutamide.[187][189] In addition to interstitial pneumonitis, there is a smaller number of published case reports of eosinophilic lung disease associated with bicalutamide.[190][191] Side effects associated with the rare lung toxicity of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).[192]
Published case reports of bicalutamide-associated lung toxicity
#
Age
Sex
Dosage
Onset
Type of injury
Outcome
Ref
1
69 years
Male
200 mg/day
6 months
Eosinophilic lung disease
Recovered
Wong et al. (1998)
2
~76 years
Male
200 mg/day
8 months
Interstitial pneumonitis
Recovered
McCaffrey & Scher (1998)
3
~82 years
Male
80 mg/day
4 weeks
Interstitial pneumonitis
Recovered
Shioi et al. (2003)
4
~72 years
Male
80 mg/day
2.5 months
Interstitial pneumonitis
Recovered, then deatha
Shioi et al. (2005)
5
84 years
Male
?
8 months
Interstitial pneumonitis
Recovered
Kobayashi et al. (2006)
6
76 years
Male
?
?
Interstitial pneumonitis
?
Gifford & DeLong (2008)
7
85 years
Male
?
4 months
Interstitial pneumonitis
Death
Kawahara et al. (2009)
8
78 years
Male
80 mg/day
8 months
Interstitial pneumonitis
Recovered
Masago et al. (2011)
9
77 years
Male
?
7 months
Interstitial pneumonitis
Death
Song et al. (2014)
10
77 years
Male
>50 mg/day
~12 months
Interstitial pneumonitis
Death
Molina Mancero et al. (2016)
11
79 years
Male
?
1 month
Interstitial pneumonitis
Death
Polatoglu et al. (2017)
12
66 years
Male
?
?
Interstitial pneumonitis
Recovered
Kim et al. (2018)
13
66 years
Male
?
?
Interstitial pneumonitis
Recovered
Derichs et al. (2018)
14
86 years
Male
150 mg/day
6 years
Eosinophilic pneumonitis
Recovered
Umeojiako & James (2019)
15
75 years
Male
?
2 weeks
Interstitial pneumonitis
Death
Maeda et al. (2019)
16
79 years
Male
?
1.5 months
Interstitial pneumonitis
Recovered
Saito (2020)
17
66 years
Male
50 mg/day
6 months
Interstitial pneumonitis
Recovered
Smith & Antonarakis (2020)
Footnotes:a = Died of pneumothorax followed by spontaneous rupture of bulla induced by previous interstitial pneumonitis 14 months after discontinuation of bicalutamide and recovery from interstitial pneumonitis. Notes: Twelve additional cases of bicalutamide-associated interstitial pneumonitis, three of which resulted in death, were observed in an 87,000-patient cohort from MedWatch (U.S.Tooltip United StatesFDATooltip Food and Drug Administration passive adverse-event reporting database) between 1998 and 2000 (0.01% incidence). The median age of the patients was 73.5 years (range 59 to 91 years), and median duration of bicalutamide exposure was 7.5 weeks (range 1 to 312 weeks). Cases of interstitial pneumonitis have also been reported in association with flutamide, nilutamide, and gonadotropin-releasing hormone (GnRH) agonists.
Risk of death
In men with early prostate cancer, bicalutamide has been shown to increase the likelihood of death due to causes other than prostate cancer.[81] This was shown in the SPCG-6Tooltip Scandinavian Prostate Cancer Group 6 substudy (n=1218) of the EPC programme, in which overall survival was significantly worse in the 150mg/day bicalutamide monotherapy group compared to the placebo/standard care group (HRTooltip hazard ratio = 1.47; 95% CITooltip confidence interval = 1.06–2.03).[81] There was also a near-significant trend toward increased overall mortality in the combined programme (n=8113) (HR = 1.16; 95% CI = 0.99–1.37; p=0.07).[81] At 5.4years of follow-up for the EPC programme, the overall incidence of death was 25.2% in the bicalutamide group and 20.5% in the placebo/standard care group.[21][79][80] This was because more bicalutamide than placebo/standard care recipients had died due to causes unrelated to prostate cancer (16.8% vs. 9.5% at 5.4-year follow-up; 10.2% vs. 9.2% at 7.4-year follow-up).[21][80][8] Bicalutamide reduced mortality due to prostate cancer, but this was not sufficient to overcome the increase in mortality due to non-prostate-cancer causes.[21][79][80] Other trials, such as NRG/RTOG 9601, have also reported increased mortality with bicalutamide.[81] Consequent to the EPC programme findings, authorization of bicalutamide for the treatment of LPC was revoked, and use of bicalutamide for this indication was discontinued.[8][80][79][193] Bicalutamide continues to be authorized and used in the treatment of LAPC and mPC, where the benefits of bicalutamide against prostate cancer outweigh any influence on non-prostate-cancer mortality.[8]
The reasons for the increased overall mortality with bicalutamide seen in the EPC programme have not been fully elucidated.[30] In any case, at 7.4-year follow-up, there were numerically more deaths from heart failure (1.2% vs. 0.6%) and gastrointestinal cancer (1.3% vs. 0.9%) in the bicalutamide group relative to placebo/standard care recipients.[8][78][194] It has been said that there was no consistent pattern suggestive of drug-related toxicity for bicalutamide and that the causes were likely a consequence of androgen deprivation:[195][196][8][78][197]
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.[195]
The increased number of deaths in bicalutamide-treated patients under watchful waiting with localized disease appears to be due to the accumulation of several small imbalances in various causes of death rather than an identifiable specific cause. However, an indirect effect from androgen receptor blockade, or some other unknown hormonally mediated effect, can neither be confirmed nor refuted with current data.[196]
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,[205] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,[206] occur much more frequently in combination with a GnRH analogue.[12][207][208] 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.[12] 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.[205] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.[209]
^"Bicalutamide"(PDF). Richmond Hill, Ontario: Nu-Pharm Inc. October 2009.
^ abBennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID12353966. An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.
^Molina Mancero G, Picón X, Di Tullio F, Ernst G, Dezanzo P, Salvado A, Chertcoff JF (October 2016). "Neumonía intersticial inducida por bloqueo androgénico máximo como tratamiento de cáncer de próstata avanzado" [Fatal interstitial lung disease associated with maximum androgen blockade. Report of one case]. Revista médica de Chile (in Spanish). 144 (10): 1356–1359. doi:10.4067/S0034-98872016001000017. PMID28074993.
^Lee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide - case report and review of the literature". Photodermatology, Photoimmunology & Photomedicine. 32 (3): 161–164. doi:10.1111/phpp.12230. PMID26663090. S2CID2761388.
^Gretarsdottir HM, Bjornsdottir E, Bjornsson ES (2018). "Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect". Case Reports in Gastroenterology. 12 (2): 266–270. doi:10.1159/000485175. ISSN1662-0631. S2CID81661015.
^ abAronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–152. ISBN978-0-08-093292-7. In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide.
^Migliari R, Muscas G, Usai E (August 1992). "Effect of Casodex on sleep-related erections in patients with advanced prostate cancer". J. Urol. 148 (2 Pt 1): 338–41. doi:10.1016/S0022-5347(17)36588-6. PMID1378907.
^Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clin Pharmacokinet. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID9592622. S2CID25200595. If used in monotherapy, libido and potency are largely preserved. Although the mechanisms to explain this are not completely understood, it seems that at the central level pure antiandrogens are unable to completely inhibit the effect of the increased amount of androgens.
^Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S (October 2011). "Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period". Gynecol. Endocrinol. 27 (10): 823–9. doi:10.3109/09513590.2010.526664. PMID21117864. S2CID20250916. Among the slight and temporary adverse events [of flutamide], most frequently reported and not requesting treatment discontinuation were headache (7.8%), respiratory tract disorders (7.0%), nausea and/or vomiting (4.0%), diarrhea (4.0%), dry skin (9.5%), and reduction of libido (4.5%).
^Venturoli S, Paradisi R, Bagnoli A, Colombo FM, Ravaioli B, Vianello F, Mancini F, Gualerzi B, Porcu E, Seracchioli R (2001). "Low-dose flutamide (125 mg/day) as maintenance therapy in the treatment of hirsutism". Horm. Res. 56 (1–2): 25–31. doi:10.1159/000048086. PMID11815724. S2CID46782286.
^ abcdefIversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6". The Journal of Urology. 172 (5 Pt 1): 1871–6. doi:10.1097/01.ju.0000139719.99825.54. PMID15540741. Abnormal liver function tests, assessed by adverse events or as clinically relevant changes in liver function parameters, were infrequent, transient and rarely severe with bicalutamide. There were no reports of bicalutamide induced fatal hepatotoxicity.
^ abTurkkan G, Dogan C, Tek B (November 2019). "Bicalutamide-associated hallucinations in a metastatic prostate cancer patient: A case report". J Oncol Pharm Pract. 26 (4): 1029–1031. doi:10.1177/1078155219886918. PMID31707924. S2CID207947815.
^Kennealey GT, Furr BJ (February 1991). "Use of the nonsteroidal anti-androgen Casodex in advanced prostatic carcinoma". Urol. Clin. North Am. 18 (1): 99–110. doi:10.1016/S0094-0143(21)01397-5. PMID1992575.
^Zanardi S, Puntoni M, Maffezzini M, Bandelloni R, Branchi D, Argusti A, Campodonico F, Turbino L, Mori M, Decensi A (1 December 2006). "A biomarker trial of intermittent, low-dose bicalutamide in subjects at high risk for prostate cancer: Updated results". Cancer Epidemiol Biomarkers Prev. 15 (12 Supplement): A145. Testosterone (T), LH, E2 and SHBG levels increased on Bic, although only T changes on both doses and LH changes on Bic 100 mg were significantly different to controls (p<0.001). Changes in circulating hormones and biomarkers were evident after 3 months, and persisted through the 6th month of treatment. No change in circulating hormones or biomarkers was observed in the control group. [...] Treatment was well tolerated, although breast pain was recorded in 0/19 (0%), 8/25 (32%) and 14/22 (64%), and gynecomastia in 0/19 (0%), 11/25 (44%) and 11/22 (50%) of subjects on no treatment, Bic 50 or 100 mg, respectively.
^Decensi A, Zanardi S, Puntoni M, Bandelloni R, Branchi D, Argusti A, Campodonico F, Turbino L, Mori M, Maffezzini M (20 June 2007). "Phase I-II trial of weekly bicalutamide in men with high PSA and negative biopsy". Journal of Clinical Oncology. 25 (18_suppl): 1500. doi:10.1200/jco.2007.25.18_suppl.1500. T, LH, estradiol and SHBG increased on Bic by 50–60%. [...] Treatment was well tolerated, mild (G1) breast pain and gynecomastia being recorded in 40% of treated subjects.
^ abMichalopoulos NV, Keshtgar MR (2012). "Images in clinical medicine. Gynecomastia induced by prostate-cancer treatment". The New England Journal of Medicine. 367 (15): 1449. doi:10.1056/NEJMicm1209166. PMID23050528. Gynecomastia occurs in up to 80% of patients who receive nonsteroidal antiandrogens (eg, bicalutamide, flutamide, or nilutamide), usually within the first 6 to 9 months after the initiation of treatment.
^Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (2007). "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study". European Urology. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID17270340.
^ abWirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13, discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID17007995.
^ abcDi Lorenzo G, Autorino R, Perdonà S, De Placido S (2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review". Lancet Oncol. 6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2. PMID16321765.
^ abcdFourcade, R.-O.; McLeod, D. (March 2004). "Tolerability of Antiandrogens in the Treatment of Prostate Cancer". UroOncology. 4 (1): 5–13. doi:10.1080/1561095042000191655. ISSN1561-0950. The risk of fatal or serious hepatic toxicity associated with flutamide was estimated to be 3 of 10,000 based on cases reported to the Food and Drug Administration in the USA [59], although others suggest that the incidence may be higher than this [57].
^ abcdVan Poppel H, Tyrrell CJ, Haustermans K, Cangh PV, Keuppens F, Colombeau P, Morris T, Garside L (May 2005). "Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer". Eur Urol. 47 (5): 587–92. doi:10.1016/j.eururo.2004.12.003. PMID15826748. 3.2. Incidence, time to onset and intensity of symptoms. Of the 51 patients, 37 (72.5%) experienced gynaecomastia and 41 (80.4%) experienced breast pain within the 12 months following initiation of bicalutamide 150 mg. Time to onset of these symptoms is illustrated in Fig. 1. Generally, gynaecomastia and breast pain were reported within the first 6 months of treatment (89.2% [33/37] and 97.6% [40/41], respectively).
^Brown JS, Rubenfeld S (1974). "Irradiation in preventing gynecomastia induced by estrogens". Urology. 3 (1): 51–3. doi:10.1016/s0090-4295(74)80060-9. PMID4812899. Infrequently, the breast hypertrophy can become so marked that it attains proportions comparable to that in female breasts.
^Deepinder F, Braunstein GD (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–95. doi:10.1517/14740338.2012.712109. PMID22862307. S2CID22938364. Treatment with estrogen has the highest incidence of gynecomastia, at 40 – 80%, anti-androgens, including flutamide, bicalutamide and nilutamide, are next, with a 40 – 70% incidence, followed by GnRH analogs (goserelin, leuprorelin) and combined androgen deprivation, both with incidences of 13% each.
^ abFradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (July 2007). "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study". Eur. Urol. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID17270340.
^Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25, discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID8560673.
^ abMorgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F (March 2001). "Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study". Histopathology. 38 (3): 195–201. doi:10.1046/j.1365-2559.2001.01077.x. hdl:11573/387981. PMID11260298. S2CID36892099.
^Higano CS (2012). "Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer". Journal of Clinical Oncology. 30 (30): 3720–5. doi:10.1200/JCO.2012.41.8509. PMID23008326.
^ abBjerklund Johansen TE, Majak M, Nesland JM (March 1994). "Testicular histology after treatment with the new antiandrogen Casodex for carcinoma of the prostate. A preliminary report". Scand. J. Urol. Nephrol. 28 (1): 67–70. doi:10.3109/00365599409180473. PMID8009196.
^ abcdefghijklmnoKolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9, discussion 80–4. doi:10.1016/S0090-4295(96)80012-4. PMID8560681. [...] In the combination study,9 the incidence of hepatic adverse events was lower in bicalutamide plus LHRH-A group than in the flutamide plus LHRH-A group (6.7% versus 12%; P = 0.07). [...] In the clinical trial program, evaluation of biochemistry assessments showed that increases in the liver function test values for serum glutamic oxaloacetic transaminase (SGOT; aspartate aminotransferase) and serum glutamic pyruvic transaminase (SGPT; alanine aminotransaminase) occurred with greater frequency in the flutamide plus LHRH-A group than in the bicalutamide plus LHRH-A group (49 [12.0%] and 28 [7.0%] patients, respectively). The difference between groups was observed for both test results that were less than twice the upper limit of normal (ULN) and for test results that were greater than two times the ULN. [\n\n] In the combination study, 77 patients (28 [7.0%], bicalutamide plus LHRH-A; 49 [12.0%], flutamide plus LHRH) had at least one liver enzyme test result (SGOT or SGPT) that exceeded twice the ULN. For these patients, there was no clear pattern to distinguish between SGOT versus SGPT changes as drug induced; changes were observed for both enzymes (either alone or together) while patients received study therapy. Of these 77 patients, 52 had an increase in SGOT and/or SGPT levels >2 ✕ ULN on only one occasion. [\n\n] Drug-induced changes were more likely when liver function test values were above the ULN at more than one assessment. This finding was observed more often for flutamide-treated patients than for bicalutamide-treated patients (17 [4.2%] vs 8 [2.0%]). Liver function test values >5 ✕ ULN (SGOT >325 U/L [patients >65 years]; SGPT >265 U/L) after the start of therapy were more frequently observed for patients who received flutamide plus LHRH-A (10 of 407 patients) [2.5%] than patients who received bicalutamide plus LHRH-A (2 of 401 patients) [0.5%].
^Jones HB, Betton GR, Bowdler AL, McFarquhar RL, Middleton BJ, Lunglmayr G (1994). "Pathological and morphometric assessment of testicular parameters in patients with metastatic prostate cancer following treatment with either the antiandrogen Casodex (ZM176,334) or bilateral orchidectomy". Urol. Res. 22 (3): 191–5. doi:10.1007/BF00571849. PMID7992465. S2CID19540140.
^Papadimitriou, Kasiani; Anagnostis, Panagiotis; Goulis, Dimitrios G. (2022). "The challenging role of antiandrogens in the management of polycystic ovary syndrome". Polycystic Ovary Syndrome. Elsevier. pp. 297–314. doi:10.1016/B978-0-12-823045-9.00013-4. ISBN9780128230459. S2CID244697776.
^ abHembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG (December 2017). "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline". Endocr Pract. 23 (12): 1437. doi:10.4158/1934-2403-23.12.1437. PMID29320642. S2CID3639218.
^ abcLee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature". Photodermatology, Photoimmunology & Photomedicine. 32 (3): 161–4. doi:10.1111/phpp.12230. PMID26663090. S2CID2761388.
^ abSasada K, Sakabe J, Tamura A, Kasuya A, Shimauchi T, Ito T, Hirakawa S, Tokura Y (2012). "Photosensitive drug eruption induced by bicalutamide within the UVB action spectrum". European Journal of Dermatology. 22 (3): 402–3. doi:10.1684/ejd.2012.1719. PMID22503957.
^Tyrrell CJ, Blake GM, Iversen P, Kaisary AV, Melezinek I (May 2003). "The non-steroidal antiandrogen, bicalutamide ('Casodex'), may preserve bone mineral density as compared with castration: results of a preliminary study". World J Urol. 21 (1): 37–42. doi:10.1007/s00345-003-0322-7. PMID12756493. S2CID13355134.
^ abSieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S (June 2004). "Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer". J. Urol. 171 (6 Pt 1): 2272–6, quiz 2435. doi:10.1097/01.ju.0000127738.94221.da. PMID15126801.
^Wadhwa VK, Weston R, Parr NJ (June 2011). "Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer". BJU Int. 107 (12): 1923–9. doi:10.1111/j.1464-410X.2010.09726.x. PMID20950306. S2CID205543615.
^Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I (2000). "Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup". The Journal of Urology. 164 (5): 1579–82. doi:10.1016/s0022-5347(05)67032-2. PMID11025708.
^ abcChodak G, Gomella L, Phung de H (September 2007). "Combined androgen blockade in advanced prostate cancer: looking back to move forward". Clin Genitourin Cancer. 5 (6): 371–8. doi:10.3816/CGC.2007.n.019. PMID17956709.
^ abcTyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration". BJU Int. 98 (3): 563–72. doi:10.1111/j.1464-410X.2006.06275.x. PMID16771791. S2CID41672303.
^ abcdefJia AY, Spratt DE (June 2022). "Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative". Int J Radiat Oncol Biol Phys. 113 (2): 316–319. doi:10.1016/j.ijrobp.2022.01.037. PMID35569476. S2CID248765294. Four other randomized trials using BICmono have also raised concerns about either lack of efficacy or even harm from this treatment approach compared with placebo or no hormone therapy. SPCG-6 randomized 1218 patients to either 150 mg of BICmono daily or placebo. In the subset of patients with LPCa managed with observation, survival was significantly worse with BIC than placebo (hazard ratio [HR], 1.47; 95% confidence interval, 1.06-2.03).10 Two other randomized trials were part of the early prostate cancer program,11 which conducted 3 randomized trials that were pooled together to determine the benefit of BICmono (SPCG-6 was one of the 3 trials). Overall, in the combined 8113 patient pooled cohort, after a median follow-up of 7 years, there was no improvement even in progression-free survival from the use of adjuvant BIC in LPCa, and there was a trend for worse overall survival (HR, 1.16; 95% confidence interval, 0.99-1.37; P = .07). [...] Although not in LPCa, NRG/RTOG 9601 demonstrated findings consistent with the prior trials.12 This trial randomized men to postprostatectomy salvage radiation therapy plus placebo versus 150 mg of BICmono daily for 2 years. After a median follow-up of 13 years, the trial showed that there were significantly more grade 3 to 5 cardiac events in the BICmono arm. In patients with less aggressive disease with lower PSAs (prostate-specific antigens; more analogous to LPCa), other-cause mortality was significantly higher in the BICmono arm. In patients with high PSAs >1.5 ng/mL (which with modern molecular positron emission tomography imaging would be expected to have high rates of regional and distant metastatic disease), a survival benefit from the addition of BIC was observed. This is consistent with results from the early prostate cancer studies that showed that only patients with more advanced disease derived benefit from BICmono.10 Thus, all the randomized evidence from 5 trials (Table 1) demonstrates that, in LPCa, BICmono had no clinically significant oncologic activity over placebo/no treatment, and consistent trends with long-term use resulted in worse survival.
^ abcdeNguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, Beckman JA, Choueiri TK (2011). "Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials". JAMA: The Journal of the American Medical Association. 306 (21): 2359–66. doi:10.1001/jama.2011.1745. PMID22147380.
^ abLuque-Ramírez M, Ortiz-Flores AE, Nattero-Chávez L, Escobar-Morreale HF (December 2020). "A safety evaluation of current medications for adult women with the polycystic ovarian syndrome not pursuing pregnancy". Expert Opin Drug Saf. 19 (12): 1559–1576. doi:10.1080/14740338.2020.1839409. PMID33070640. S2CID224784192.
^Eri LM, Urdal P (1995). "Effects of the nonsteroidal antiandrogen Casodex on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia". Eur Urol. 27 (4): 274–9. doi:10.1159/000475180. PMID7544732.
^Sawazaki H, Araki D, Kitamura Y, Yagi K (June 2020). "Metabolic changes with degarelix vs leuprolide plus bicalutamide in patients with prostate cancer: a randomized clinical study". World J Urol. 38 (6): 1465–1471. doi:10.1007/s00345-019-02937-x. PMID31482294. S2CID201815162.
^Baldani DP, Skrgatic L, Ougouag R, Kasum M (February 2018). "The cardiometabolic effect of current management of polycystic ovary syndrome: strategies of prevention and treatment". Gynecol Endocrinol. 34 (2): 87–91. doi:10.1080/09513590.2017.1381681. PMID28944709. S2CID205631980.
^Klil-Drori AJ, Yin H, Tagalakis V, Aprikian A, Azoulay L (July 2016). "Androgen Deprivation Therapy for Prostate Cancer and the Risk of Venous Thromboembolism". Eur. Urol. 70 (1): 56–61. doi:10.1016/j.eururo.2015.06.022. PMID26138040.
^Edmunds K, Tuffaha H, Galvão DA, Scuffham P, Newton RU (May 2020). "Incidence of the adverse effects of androgen deprivation therapy for prostate cancer: a systematic literature review". Support Care Cancer. 28 (5): 2079–2093. doi:10.1007/s00520-019-05255-5. hdl:10072/391356. PMID31912360. S2CID209896933.
^Nead KT, Boldbaatar N, Yang DD, Sinha S, Nguyen PL (April 2018). "Association of Androgen Deprivation Therapy and Thromboembolic Events: A Systematic Review and Meta-analysis". Urology. 114: 155–162. doi:10.1016/j.urology.2017.11.055. PMID29352986. S2CID4858605.
^ abcdefgMcLeod DG (1997). "Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer". Oncologist. 2 (1): 18–27. doi:10.1634/theoncologist.2-1-18. PMID10388026. Incidences of abnormal liver function test results have been variously reported from 2%-33% in nilutamide groups [13, 32, 33, 45] and from 4%-62% in flutamide groups [5, 7, 9, 11, 34, 38-40, 48] in trials of monotherapy and CAB. [...] In the double-blind, comparative study of flutamide plus LHRH-A versus bicalutamide plus LHRH-A, elevated transaminases occurred in slightly more patients in the flutamide group than in the bicalutamide group (10% versus 6%; p = 0.07). This increased incidence was also seen for patients with greatly elevated (>5× normal) transaminase values (2% versus 0.5%) [22, 46].
^Schellhammer, Paul (December 1996). "Drug Evaluation Oncologic, Endocrine & Metabolic: Bicalutamide (Casodex™)". Expert Opinion on Investigational Drugs. 5 (12): 1707–1722. doi:10.1517/13543784.5.12.1707. eISSN1744-7658. ISSN1354-3784. Decreases in haemoglobin have been associated with flutamide therapy; more modest reductions occurred in patients who received bicalutamide in the monotherapy studies. In the combination study, flutamide therapy appeared to have a more profound negative effect on haemoglobin synthesis than did bicalutamide [24].
^See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, et al. (August 2002). "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program". The Journal of Urology. 168 (2): 429–35. doi:10.1016/S0022-5347(05)64652-6. PMID12131282.
^ abcBlackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 (Suppl 2): 96–104. doi:10.1159/000473847. PMID8717470.
^ abSchellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G (January 1996). "Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Casodex Combination Study Group". Urology. 47 (1A Suppl): 54–60, discussion 80–4. doi:10.1016/s0090-4295(96)80010-0. PMID8560679. The tolerability evaluation included 808 patients (401 in the bicalutamide plus LHRH-A group and 407 in the flutamide plus LHRH-A group) and was performed after a median follow-up of 49 weeks. Five patients refused therapy; 88 patients (32 [8.0%] in the bicalutamide plus LHRH-A group and 56 [13.8%] in the flutamide plus LHRH-A group) had study therapy withdrawn because of safety reasons (Table II). [...] TABLE II. Adverse events leading to withdrawal: [...] Liver function abnormalities: Bicalutamide plus LHRH-A (n = 401): 6 [1.5%]; Flutamide plus LHRH-A (n = 407): 8 [2.0%]. [...]
^See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ (August 2002). "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program". J Urol. 168 (2): 429–35. doi:10.1016/S0022-5347(05)64652-6. PMID12131282.
^ abCarvalho RM, Santos LD, Ramos PM, Machado CJ, Acioly P, Frattini SC, Barcaui CB, Donda AL, Melo DF (October 2022). "Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know". J Cosmet Dermatol. 21 (10): 4171–4175. doi:10.1111/jocd.14773. PMID35032336. S2CID253239337.
^Ismail FF, Meah N, Trindade de Carvalho L, Bhoyrul B, Wall D, Sinclair R (November 2020). "Safety of oral bicalutamide in female pattern hair loss: A retrospective review of 316 patients". J Am Acad Dermatol. 83 (5): 1478–1479. doi:10.1016/j.jaad.2020.03.034. PMID32213304. S2CID214683043.
^ abBlackledge G, Kolvenbag G, Nash A (January 1996). "Bicalutamide: a new antiandrogen for use in combination with castration for patients with advanced prostate cancer". Anticancer Drugs. 7 (1): 27–34. doi:10.1097/00001813-199601000-00002. PMID8742095.
^Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA (October 2013). "Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer". Clin Cancer Res. 19 (19): 5505–12. doi:10.1158/1078-0432.CCR-12-3327. PMC4086643. PMID23965901. There were few grade 2 or 3 adverse events associated with bicalutamide (Table 3). All grade 3 liver enzyme abnormalities (elevation in AST, bilirubin, and alkaline phosphatase) were documented in 1 patient with known liver metastases who had progressed on therapy. Thus, it remains unclear whether these laboratory findings were attributable to bicalutamide therapy or disease progression.
^Trüeb RM, Luu NC, Uribe NC, Régnier A (December 2022). "Comment on: Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know". J Cosmet Dermatol. 21 (12): 7200–7201. doi:10.1111/jocd.14936. PMID35332669. S2CID247677549. Indeed, due to the minimal biological importance of androgens in women, the adverse effects of bicalutamide are few. And yet, bicalutamide has been associated with elevated liver enzymes, and as of 2021, there have been 10 case reports of liver toxicity associated with bicalutamide, with fatality occurring in 2 cases.2
^ abIkemoto I, Kiyota H, Abe K, Hasegawa T, Ohishi Y, Aizawa Y (20 May 2000), "ビカルタミドにより惹起された重症肝障害" [Bicalutamide-induced Liver Toxicity in a Patient with Prostate Cancer], 臨床泌尿器科 [Rinsho Hinyokika (Clinical Urology)], 54: 489–491, doi:10.11477/mf.1413902997
^Craig JV, Furr B (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 356–. ISBN978-1-59259-152-7. A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).
^ abKolvenbag, Geert J. C. M.; Furr, Barrington J.A. (2009). "Nonsteroidal Antiandrogens". Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN978-1-60761-471-5. Differences between the NSAAs are also apparent with respect to liver toxicity. Abnormal liver-function tests have been reported with all three NSAAs. The incidence of abnormalities varies widely, from 2–3% with nilutamide (67,94,95) and 4–62% with flutamide (45,69,91,96–98). Many, but not all, cases may be at least partly due to underlying diseases and/or concomitant drug therapy. In the double-blind comparative study of flutamide and bicalutamide, the incidence of elevated transaminases was higher, but not significantly so, in the flutamide group (56). Symptomatic and, in some cases, serious hepatotoxicity has also been reported for NSAAs. It has been estimated that the risk of severe, potentially fatal, hepatic failure with flutamide is 3/10000 patients (99). Nilutamide hepatotoxicity is less well-documented, but can also have a fatal outcome (100).
^Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opin Drug Saf. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID25270521. S2CID207488100. Hepatotoxicity is a well-known complication of treatment with non-steroidal antiandrogens, as well as with Cyproterone acetate. The spectrum of drug-induced liver alterations is broad and encompasses the whole range of hepatic abnormalities. The incidence of abnormal liver-function tests has been reported in variable percentages, ranging from 4 to 62% of the patients treated with Flutamide in several trials comparing Flutamide, as part of MAB, versus castration [56-58].
^Bessone F, Lucena MI, Roma MG, Stephens C, Medina-Cáliz I, Frider B, Tsariktsian G, Hernández N, Bruguera M, Gualano G, Fassio E, Montero J, Reggiardo MV, Ferretti S, Colombato L, Tanno F, Ferrer J, Zeno L, Tanno H, Andrade RJ (February 2016). "Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases". Liver Int. 36 (2): 302–10. doi:10.1111/liv.12899. hdl:11336/52496. PMID26104271. S2CID33393791.
^Gava, Giulia; Seracchioli, Renato; Meriggiola, Maria Cristina (2017). "Therapy with Antiandrogens in Gender Dysphoric Natal Males". Endocrinology of the Testis and Male Reproduction. pp. 1199–1209. doi:10.1007/978-3-319-44441-3_42. ISBN978-3-319-44440-6. ISSN2510-1927.
^Andriole, Gerald L. (1996). "Discussion session: Clinical trials of bicalutamide as monotherapy for prostate cancer". Urology. 47 (1): 48–53. doi:10.1016/S0090-4295(96)80009-4. ISSN0090-4295.
^Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". European Reviews for Medical and Pharmacological Sciences. 21 (1 Suppl): 69–77. PMID28379593.
^Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA (July 2009). "Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity". Toxicology and Applied Pharmacology. 238 (2): 150–9. Bibcode:2009ToxAP.238..150K. doi:10.1016/j.taap.2009.05.007. PMID19442681.
^Boelsterli UA, Ho HK, Zhou S, Leow KY (October 2006). "Bioactivation and hepatotoxicity of nitroaromatic drugs". Current Drug Metabolism. 7 (7): 715–27. doi:10.2174/138920006778520606. PMID17073576.
^Coe KJ, Nelson SD, Ulrich RG, He Y, Dai X, Cheng O, Caguyong M, Roberts CJ, Slatter JG (July 2006). "Profiling the hepatic effects of flutamide in rats: a microarray comparison with classical aryl hydrocarbon receptor ligands and atypical CYP1A inducers". Drug Metab Dispos. 34 (7): 1266–75. doi:10.1124/dmd.105.009159. PMID16611858. S2CID8866215.
^Gretarsdottir, Helga M.; Bjornsdottir, Elin; Bjornsson, Einar S. (2018). "Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect". Case Reports in Gastroenterology. 12 (2): 266–270. doi:10.1159/000485175. ISSN1662-0631. S2CID81661015.
^Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID25270521. S2CID207488100.
^ abWu B, Shen P, Yin X, Yu L, Wu F, Chen C, Li J, Xu T (February 2023). "Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System". Br J Clin Pharmacol. 89 (2): 440–448. doi:10.1111/bcp.15336. PMID35349180. S2CID247777754.
^Wong PW, Macris N, DiFabrizio L, Seriff NS (February 1998). "Eosinophilic lung disease induced by bicalutamide: a case report and review of the medical literature". Chest. 113 (2): 548–50. doi:10.1378/chest.113.2.548. PMID9498983.
^Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA (June 2004). "Drug-induced pulmonary fibrosis". Saudi Medical Journal. 25 (6): 700–6. PMID15195196.
^Nargund VH, Raghavan D, Sandler HM (17 January 2015). Urological Oncology. Springer. pp. 823–. ISBN978-0-85729-482-1. On the other hand, the 150 mg dose of bicalutamide has been associated with some safety concerns, such as a higher death rate when added to active surveillance in the early prostate cancer trialists group study [29], which has led the United States and Canada to recommend against prescribing the 150 mg dose [30].
^ abIversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J (2006). "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years". Scandinavian Journal of Urology and Nephrology. 40 (6): 441–52. doi:10.1080/00365590601017329. PMID17130095. S2CID25862814.
^Wibowo E, Schellhammer P, Wassersug RJ (January 2011). "Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy". J Urol. 185 (1): 17–23. doi:10.1016/j.juro.2010.08.094. PMID21074215.
^Wibowo E, Wassersug RJ (September 2013). "The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy". Crit Rev Oncol Hematol. 87 (3): 224–38. doi:10.1016/j.critrevonc.2013.01.006. PMID23484454.
^Mason M (August 2006). "What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care?". Journal of Cancer Research and Clinical Oncology. 132: S27-35. doi:10.1007/s00432-006-0134-4. PMID16896883. S2CID19685819.
