Showing papers on "Bicalutamide published in 1996"

Randomised Study of Casodex 50 Mg Monotherapy vs Orchidectomy in the Treatment of Metastatic Prostate Cancer

Abstract: The effect of Casodex (ICI 176,334), a new, once-daily, selective antiandrogen, given as 50 mg monotherapy, was compared with orchidectomy in a randomised, multicentre, open study in 376 patients with metastatic prostate cancer. At 3 months, PSA was reduced by 86% in the Casodex group and by 96% in the orchidectomy group. Treatment failed in 51 patients in the orchidectomy group and 66 showed a subjective response. Treatment failed in 86 patients treated with Casodex and 40 patients showed a subjective response. Patients treated with Casodex maintained their sexual interest better than those in the orchidectomy group. Median survival was significantly longer in the orchidectomy group. Casodex was well-tolerated. The most likely reason for the differences between the groups regarding time to treatment failure and survival is that the dose of Casodex was too small. Further studies with higher doses of Casodex are in progress.

Regulation of steroid glucuronosyltransferase activities and transcripts by androgen in the human prostatic cancer LNCaP cell line

Abstract: Although much attention has been focused on the synthesis of dihydrotestosterone (DHT), the inactivation and elimination of active androgens can also be key points in regulating androgen levels in tissues such as the prostate. Recent data suggest that 5alpha-reduced C19 steroids can be converted to glucuronide derivatives in the human prostate, leading to complete inactivation of these steroids. These results are supported by the recent finding of at least two steroid uridine diphosphoglucuronosyltransferase (UGT) enzymes in the prostate as well as in the human prostatic cancer LNCaP cell line. To ascertain the role of UGTs in regulating active steroid levels, we investigated the modulation of UGT levels in response to steroid treatments in LNCaP cells. Results demonstrate the down-regulation of UGT activities specific for 3-hydroxysteroids and 17-hydroxy-steroids after treatment with androgens and estrogens. Treating the cells with DHT or R1881 for 7 days inhibited UGT activity by 60%; however, 80% of the total activity was recovered after 5 days in the absence of the androgens. The inhibition of UGT activities by DHT and R1881 increases with the time of incubation and with increasing concentrations of the androgens used. The decrease in UGT enzyme activity occurred in parallel with a diminution in UGT transcript levels, as observed in Northern blot analyses. A correlation between the effect of steroids on the androgen-dependent growth response of LNCaP cells, the secretion of prostate-specific antigen, and the inhibition of UGT activities was clearly demonstrated, which implicates the androgen signaling pathway. Treating cells with Casodex, an androgen antagonist that binds the mutated androgen receptor expressed in LNCaP cells, partially blocked the androgen- and estrogen-induced decrease in UGT activity, suggesting that the regulation of UGT levels involves the androgen receptor. In addition to the formation of DHT, the inactivation of steroids by glucuronidation, which is regulated by steroids themselves, is an important mechanism controlling the level of androgens in the prostate.

A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate carcinoma: Analysis of time to progression

Abstract: BACKGROUND A randomized, multicenter trial, double-blind for antiandrogen therapy, compared the antiandrogens bicalutamide and flutamide, each combined with luteinizing hormone–releasing hormone analogue therapy (LHRH-A) in 813 patients with Stage D2 prostate carcinoma. An analysis of time to progression (median follow-up, 95 weeks) was performed to augment previous analyses of time to treatment failure and time to death. METHODS Patients were randomly assigned 1:1 to double-blind antiandrogen therapy, receiving either bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), and were assigned 2:1 to LHRH-A with goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). The primary endpoint of the trial was time to treatment failure, defined as an adverse event leading to withdrawal of randomized therapy, objective progression, death, or withdrawal from study therapy for any reason. Secondary endpoints were time to death, quality of life, and subjective response. The current analysis of time to progression included progression data collected prospectively for 561 patients (69%) and retrospectively for 252 patients (31%). RESULTS Disease progression occurred for 223 of 404 patients (55%) in the bicalutamide plus LHRH-A group and for 235 of 409 patients (58%) in the flutamide plus LHRH-A group. The hazard ratio for time to progression of bicalutamide plus LHRH-A to that of flutamide plus LHRH-A was 0.9 (two-sided 95% confidence interval [CI], 0.75 to 1.08; P = 0.26). The upper one-sided 95% CI was 1.05, which met the definition of equivalence (<1.25). CONCLUSIONS At a median follow-up time of 95 weeks, bicalutamide plus LHRH-A and flutamide plus LHRH-A had equivalent time to progression. Cancer 1996;78:2164-9.

Bicalutamide: a new antiandrogen for use in combination with castration for patients with advanced prostate cancer.

Abstract: Maximum androgen blockade, a relatively recent development in the treatment of prostate cancer, combines medical or surgical castration with antiandrogen therapy. A large randomized study comparing the non-steroidal antiandrogen, bicalutamide, with flutamide, each in combination with luteinizing hormone-releasing hormone (LHRH) analogs, showed that after a median follow-up of 49 weeks, the time to treatment failure was significantly longer for the bicalutamide patients compared with the flutamide patients (p = 0.005). After a median follow up to 95 weeks, bicalutamide in combination with LHRH analog therapy produced at least equivalent efficacy with flutamide in combination with LHRH analog therapy in terms of time to treatment failure and equivalent efficacy in terms of survival. The tolerability profile of bicalutamide, as based on reported findings and a literature review, indicates a superior tolerability to that of currently available antiandrogens, particularly with respect to diarrhea with a low incidence of treatment-related withdrawals.

Prostate cancer: current and evolving strategies

Abstract: The staging, screening and diagnosis, and treatment of prostate cancer are discussed. Prostate cancer kills about 40,000 men in the United States each year. Signs and symptoms range from dysuria to features of advanced metastatic disease. The American Urological System of staging prostate cancer designates four stages, A through D. The tumor is graded histologically with the Gleason scale. Methods used in the screening and diagnosis of prostate cancer include digital rectal examination, the prostate-specific antigen (PSA) assay, biopsy, transrectal ultrasonography, and determination of PSA density, velocity, and age specificity. The value of screening and treatment remains controversial because tumors are generally slow-growing and conclusive data showing an effect on survival time are lacking. Treatment methods consist of prostatectomy, radiation therapy, and hormonal drug therapy or bilateral orchiectomy. The choice is influenced primarily by the stage of the disease but also by the patient's age, physical condition, and response to prior therapy. Patients with stage A or B disease are considered for prostatectomy or radiation therapy. The primary treatment for stage C disease is radiation therapy. For stage D, the main approaches are watchful waiting and bilateral orchiectomy or hormonal drug therapy to reduce androgenic stimulation of prostate tissue. Long-term survival rates are high for stages A and B and considerably lower for stages C and D. Prostate cancer responds to estrogens, but adverse effects are frequent and potentially severe. Luteinizing hormone-releasing hormone agonists (leuprolide and goserelin) are as effective as estrogens but have less toxicity; a disadvantage of these agents is an initial flaring of the disease. Other hormonal agents used include antiandrogens-progestins, flutamide, and bicalutamide. Secondary hormonal treatments (aminoglutethimide and ketoconazole) are less effective than initial hormonal therapy. Antineoplastic agents have little or no effectiveness in prostate cancer. Although the value of screening for and treating prostate cancer continues to be debated, many experts recommend annual screening for all men over 50. Research to identify more effective drugs for treating advanced disease continues.

Absence of hepatic enzyme induction in prostate cancer patients receiving "Casodex" (bicalutamide

Abstract: The potential for hepatic enzyme induction by bicalutamide ('Casodex') was assessed in an open study in prostate cancer patients. A single, oral dose of antipyrine 1000 mg was given before and after 12 weeks' bicalutamide therapy [once daily 50 mg (n = 7) or 150 mg (n = 11)] and its pharmacokinetics and metabolism were determined. Plasma or saliva samples were taken for the measurement of antipyrine concentration. Urine samples were assayed for antipyrine and its three major metabolites. With bicalutamide 50 mg, plasma antipyrine concentrations were maximal between 2 and 4 h after administration, declined in a log-linear manner and were unaffected by bicalutamide therapy; with bicalutamide 150 mg, saliva antipyrine concentrations were maximal between 2 and 4 h, declined in a log-linear manner, and were also unaffected by bicalutamide therapy. Antipyrine half-life was 16.3% shorter after bicalutamide 50 mg (p < 0.05); a small decrease (13.5%) in half-life after bicalutamide 150 mg was not statistically significant. A small reduction (18.6%, p < 0.05) in the AUCinfinity for antipyrine was noted after bicalutamide 150 mg. A statistically significant reduction in antipyrine recovery was seen with the lower bicalutamide dose (23.7%, p < 0.05). The statistically significant changes were small in absolute terms and showed no dose-response relationship. Bicalutamide does not significantly induce the hepatic enzymes responsible for antipyrine metabolism and has no obvious potential for producing clinically significant drug interactions due to enzyme induction.

Clinical early phase II study of bicalutamide (Casodex) in patients with prostatic cancer

Abstract: To investigate the efficacy and safety of bicalutamide (Casodex) with its clinically recommended dose, the randomized early phase II study was performed in 124 patients with prostatic cancer (stage C, D). The patients were given 50, 80 or 100 mg of bicalutamide orally once a day in fixed doses for 12 weeks; 122 patients were eligible for evaluation. The overall response rate was 50.0% (20/40), 61.0% (25/41) and 53.7% (22/41) in the 50 mg, 80 mg and 100 mg groups, respectively. The response rate in prostate lesion, bone and lymph node metastases was slightly higher in the 80 mg group than in the 50 mg and 100 mg groups. The proportion of patients showing a response with regard to serum PSA (CR and PR) was 84.2, 92.7 and 97.6% in the 50, 80 and 100 mg groups, respectively. The incidence of adverse reactions was 65.0, 61.0 and 61.0% in the 50, 80 and 100 mg groups, respectively, and there was no significant difference in overall safety rating in the three groups. Frequent adverse reactions were gynecomastia and breast pain. Only one patient in the 80 mg group was withdrawn due to shortness of breath. Serum concentrations of LH, testosterone and estradiol increased significantly after treatment. Bicalutamide was concluded to be effective and well tolerated in patients with prostatic cancer, and its recommended dose was 80 mg once daily.

[Phase I study of bicalutamide (Casodex), a nonsteroidal antiandrogen in patients with prostatic cancer].

Abstract: A phase I study (open trial) of bicalutamide (Casodex), a non-steroidal antiandrogen, was conducted on 16 patients with prostatic cancer (stage C to D). The patients were given 10, 30, 50, 80 or 100 mg of bicalutamide orally daily for 12 weeks. Adverse reactions were observed in 8 out of 16 patients, but almost all were mild. Breast pain, gynecomastia and hot flushes were observed in 6 patients. Adverse reactions regarding liver function tests were observed in 3 patients. These were increased glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), alkaliphosphatase (AL-P) or gamma guanosine 5'-triphosphate (gamma-GTP). However, during or after the treatment period the elevated values were reversed to the pretreatment level. In terms of efficacy, anti-tumor effect was observed in 1 or 2 patients at each dose. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and estradiol increased during treatment. Plasma concentrations of the R (-) enantiomer, which has antiandrogenic activity, reached the steady state 6-8 weeks after the initiation of treatment; its apparent plasma elimination half-life observed following repeated administration was 8.4 +/- 1.1 days. In conclusion, bicalutamide (10-100 mg od) is considered to be tolerated well enough to be administered to patients with prostatic cancer and has shown evidence of anti-tumor effect.

Drug Evaluation Oncologic, Endocrine & Metabolic: Bicalutamide (Casodex™)

Abstract: Bicalutamide (Casodex™) is a relatively new non-steroidal antiandrogen indicated for use in combination therapy with castration for the treatment of advanced prostate cancer. Developed from a series of non-steroidal compounds related to flutamide, bicalutamide is a potent, orally active, well tolerated anti-androgen with a half-life compatible with once-daily administration. In the clinical programme in prostatic cancer, patients were exposed to bicalutamide in doses ranging from 10 - 600 mg. Doses of 10 - 200 mg have been shown to have intrinsic activity in terms of producing subjective improvement and objective responses, and daily doses of up to 600 mg are currently being evaluated. Results of monotherapy studies reveal that 50 mg of bicalutamide is less effective than castration in patients with advanced disease; Phase III monotherapy studies are ongoing to compare 150 mg of bicalutamide with castration. In monotherapy studies, both 50 mg and 150 mg of bicalutamide have an advantage over castration in...