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Peter Iversen - One of the best experts on this subject based on the ideXlab platform.

  • antiandrogen monotherapy in patients with localized or locally advanced prostate cancer final results from the Bicalutamide early prostate cancer programme at a median follow up of 9 7 years
    BJUI, 2010
    Co-Authors: Peter Iversen, T Morris, David G Mcleod, William A See, Jon Armstrong, Manfred P Wirth
    Abstract:

    Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To evaluate the efficacy and tolerability of Bicalutamide 150 mg once-daily as immediate hormonal therapy in patients with prostate cancer or as adjuvant to radical prostatectomy or radiotherapy. PATIENTS AND METHODS In all, 8113 patients with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) were enrolled in three complementary, double-blind, placebo-controlled trials. Patients were randomized to receive standard care plus either oral Bicalutamide 150 mg once-daily or oral placebo. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collated from individual trials and evaluated in a combined analysis. RESULTS Overall, at a median follow-up of 9.7 years, Bicalutamide significantly improved PFS (hazard ratio 0.85, 95% confidence interval 0.79–0.91; P= 0.001). Compared with placebo there was no difference in OS (hazard ratio 1.01, P= 0.77). Patients who derived benefit from Bicalutamide in terms of PFS were those with locally advanced disease, with OS significantly favouring Bicalutamide in patients with locally advanced disease undergoing radiotherapy (P= 0.031). Patients with localized disease showed no clinically or statistically significant improvements in PFS; there was a survival trend in favour of placebo in patients with localized disease undergoing watchful waiting (P= 0.054). The overall tolerability of Bicalutamide was consistent with previous analyses, with breast pain (73.7%) and gynaecomastia (68.8%) the most frequently reported adverse events in patients randomized to Bicalutamide. CONCLUSIONS Bicalutamide 150 mg, either as monotherapy or adjuvant to standard care, improved PFS in patients with locally advanced prostate cancer, but not in patients with localized disease. A pre-planned subset analysis showed a benefit for OS in patients with locally advanced disease undergoing radiotherapy. Bicalutamide 150 mg might represent an alternative for patients with locally advanced prostate cancer considering androgen-deprivation therapy.

  • The Early Prostate Cancer program: Bicalutamide in nonmetastatic prostate cancer
    Expert review of anticancer therapy, 2008
    Co-Authors: Peter Iversen, Martin Andreas Røder
    Abstract:

    The Early Prostate Cancer program is investigating the addition of Bicalutamide 150 mg to standard care for localized or locally advanced, nonmetastatic prostate cancer. The third program analysis, at 7.4 years' median follow-up, has shown that Bicalutamide 150 mg does not benefit patients with localized disease, but does confer significant progression-free survival benefits in patients with locally advanced disease, irrespective of standard care received. In patients receiving radiotherapy for locally advanced disease, Bicalutamide 150 mg significantly reduced the risk of death by 35%; the magnitude of this benefit compares favorably with that of adjuvant luteinizing hormone-releasing hormone agonist therapy in a similar population. Bicalutamide 150 mg represents an alternative to castration for patients with locally advanced disease who wish to avoid the side effects associated with castration.

  • 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
    BJUI, 2006
    Co-Authors: C Tyrrell, Peter Iversen, Teuvo L J Tammela, John Anderson, Thomas Bjork, A V Kaisary, T Morris
    Abstract:

    OBJECTIVE To evaluate the pharmacokinetics, tolerability and effect on endocrinology of Bicalutamide given as once-daily monotherapy at doses of > 150 mg to patients with locally advanced (MO) or metastatic (M1) prostate cancer, with efficacy as a secondary endpoint. PATIENTS AND METHODS Patients were initially enrolled to receive Bicalutamide 300 mg in a non-randomized phase, after which further patients were randomized to higher Bicalutamide doses (in 150 mg increments) or castration. Overall, 248 patients received Bicalutamide at 300 mg (21), 450 mg (95) or 600 mg (42), or castration (90). RESULTS Systemic exposure to Bicalutamide stabilised at a dose of approximate to 300 mg, as determined by pharmacokinetic analysis. The tolerability of high doses of Bicalutamide was similar to that of the 150 mg dose, with no increase in the incidence of adverse events. Patients receiving Bicalutamide had early increases in the mean levels of oestradiol, testosterone and luteinizing hormone, which were maintained throughout the study. Levels of these hormones rapidly decreased in the castration group and remained low. From baseline (first day of treatment) to 12 weeks there was an equivalent reduction in prostate-specific antigen (PSA) levels across all four groups. At a median follow-up of 5 years, there was no significant survival difference between patients who received Bicalutamide and those who received castration, either in M0 or M1 disease. CONCLUSION The low median PSA level (180 ng/mL) of patients with M1 disease might account for the lack of survival difference between the treatment groups. Further studies are needed to assess whether high-dose Bicalutamide monotherapy can provide equivalent efficacy to castration in patients with M1 prostate cancer. (Less)

  • Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer
    BJUI, 2006
    Co-Authors: David G Mcleod, Peter Iversen, T Morris, William A See, Jon Armstrong, Manfred P Wirth
    Abstract:

    OBJECTIVE To evaluate, in the ongoing Early Prostate Cancer (EPC) trial programme, the efficacy and tolerability of Bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer. PATIENTS AND METHODS The EPC programme comprises three randomized, double-blind, placebo-controlled trials designed for combined analysis. Following standard care, 8113 men with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) received oral Bicalutamide 150 mg once daily or oral placebo. The primary endpoints were progression-free survival (PFS) and overall survival. RESULTS The large EPC trial programme is defining men who benefit or do not from early or adjuvant antiandrogen therapy. At a median follow-up of 7.4 years, in localized disease there is no benefit to PFS by adding Bicalutamide to standard care, and there is a trend (hazard ratio, HR, 1.16; 95% confidence intervals, CI, 0.99–1.37; P = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting. However, in locally advanced disease, Bicalutamide significantly improved PFS irrespective of standard care. Bicalutamide significantly improved overall survival in patients receiving radiotherapy (HR 0.65; 95% CI 0.44–0.95; P = 0.03); this was driven by a lower risk of prostate cancer-related deaths. Bicalutamide produced a trend towards improved overall survival in patients with locally advanced disease otherwise undergoing watchful waiting (HR 0.81; 95% CI 0.66–1.01; P = 0.06). No survival difference was evident in the prostatectomy subgroup. CONCLUSIONS This ongoing programme is clarifying the role of early or adjuvant antiandrogen therapy in prostate cancer. Patients with localized disease do not appear to derive clinical benefit from added Bicalutamide. However, adding Bicalutamide 150 mg to standard care provides significant clinical benefits in patients with locally advanced prostate cancer, irrespective of primary therapy.

  • 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, 2004
    Co-Authors: Peter Iversen, Peter Klarskov, Janerik Johansson, Par Lodding, Olavi Lukkarinen, Per Lundmo, Teuvo L J Tammela, Ilker Tasdemir, Tom Morris, Kevin Carroll
    Abstract:

    ABSTRACTPurpose:: We evaluated the benefits of adding 150 mg Bicalutamide to standard care, that is radical prostatectomy, radiotherapy or watchful waiting (WW), in patients with localized or locally advanced prostate cancer.Materials and Methods:: A total of 1,218 men with T1–4, M0, any N prostate cancer were recruited from 62 Scandinavian centers and randomized 1:1 to 150 mg Bicalutamide or placebo plus standard care. Primary end points were progression-free survival (PFS) and overall survival.Results:: At a median 5.3-year followup patients with locally advanced disease had improved survival with Bicalutamide (HR 0.68, 95% CI 0.50 to 0.92), while those with localized disease had decreased survival with Bicalutamide (HR 1.47, 95% CI 1.06 to 2.03). Bicalutamide significantly improved PFS, decreasing the risk of disease progression by 43% compared with placebo (HR 0.57, 95% CI 0.48 to 0.68, p <0.0001). The rate of events was 35.4% for Bicalutamide and 46.2% for placebo. Patients with locally advanced dise...

G J Kolvenbag - One of the best experts on this subject based on the ideXlab platform.

  • Bicalutamide dosages used in the treatment of prostate cancer.
    The Prostate, 1999
    Co-Authors: G J Kolvenbag, Anthony Nash
    Abstract:

    BACKGROUND Androgen deprivation is often used for the treatment of patients with prostate cancer. Androgen deprivation can be achieved by surgical castration or medical castration, with or without using an antiandrogen. Each of these treatments may be used alone, or an antiandrogen may be used alongside castration to produce combined androgen blockade therapy. METHODS The nonsteroidal antiandrogen, Bicalutamide (Casodex®), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50-mg once-daily dose of Bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150-mg once-daily as monotherapy in the treatment of prostate cancer. RESULTS The choice of the 50-mg dose of Bicalutamide when used in combined androgen blockade is supported by four main arguments. First, Bicalutamide 50 mg is at least equivalent to, if not better than, flutamide 750 mg in terms of receptor affinity, potency, and favorable plasma concentration profile. Second, the reduction in testosterone concentrations produced by medical or surgical castration decreases the potential competition between Bicalutamide and testosterone for androgen receptors in prostate cells, allowing the use of a lower dose of antiandrogen in combined androgen blockade than is necessary in monotherapy. Third, Bicalutamide 50 mg has an excellent tolerability profile. Fourth, at the 50-mg dose, Bicalutamide plus luteinizing hormone-releasing hormone analogue was equivalent to flutamide plus luteinizing hormone-releasing hormone analogue, although there was a trend towards longer survival with Bicalutamide. Furthermore, investigations of higher doses of Bicalutamide have justified evaluation of Bicalutamide 150 mg as monotherapy. First, pharmacodynamic studies reveal an increasing prostate-specific antigen response with increasing dose, which appears to plateau at a dose of around 150–200 mg. Second, in an analysis with 31% mortality, Bicalutamide 150 mg appeared to have equivalent efficacy compared with castration in terms of survival in patients with nonmetastatic prostate cancer. CONCLUSIONS On the basis of available data, Bicalutamide 50 mg is an appropriate dose to use in combined androgen blockade, while 150 mg is being evaluated in ongoing clinical trials as a suitable dose for monotherapy. Prostate 39:47–53, 1999. © 1999 Wiley-Liss, Inc.

  • Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development.
    The Prostate, 1998
    Co-Authors: G J Kolvenbag, G. R. P. Blackledge, Karen Gotting-smith
    Abstract:

    BACKGROUND Bicalutamide (Casodex®) is a new nonsteroidal antiandrogen developed for use in patients with prostate cancer. The efficacy and tolerability of Bicalutamide as monotherapy and as combination therapy for patients with advanced prostate cancer have been evaluated in randomized clinical trials. Clinical trials are currently in progress to further evaluate Bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first-line therapy in patients with early-stage disease. METHODS A review of published trials of Bicalutamide focusing on dose-ranging investigations, phase II and phase III monotherapy trials, a phase III trial of combined androgen blockade, and a safety overview. RESULTS In dose-ranging trials, Bicalutamide doses of 10-200 elicited biochemical, objective, and subjective responses; higher Bicalutamide doses (up to 600 mg) have also been evaluated. A 50-mg daily dose of Bicalutamide was initially evaluated as monotherapy in phase II and phase III trials; in subsequent trials, a 150-mg daily dose was investigated. A 150-mg daily dose is considered to provide equivalent survival outcome compared with castration in patients with locally advanced prostate cancer, whereas the benefits of a better quality of life and better palliation with the 150-mg daily Bicalutamide dose relative to castration in patients with metastatic disease needs to be balanced against the small shortfall (median difference, 42 days) in survival. In combination with a luteinizing hormone-releasing hormone agonist analogue (LHRH-A), a 50-mg daily dose of Bicalutamide has equivalent efficacy to a corresponding flutamide (250 mg three times daily) combination regimen. Treatment with the Bicalutamide combination regimen resulted in a longer median survival than with the flutamide combination regimen. Bicalutamide is well tolerated when used as monotherapy or in combination with a LHRH-A. The benefits of Bicalutamide as monotherapy include retention of libido and sexual potency and as combination therapy a lower incidence of diarrhea relative to flutamide. CONCLUSIONS A 50-mg daily dose of Bicalutamide is sufficient when given in combination with an agent, such as a LHRH-A, that lowers serum testosterone, but higher doses of Bicalutamide may be needed when the drug is given as monotherapy. Bicalutamide, 50-mg daily, is a logical first choice for antiandrogen therapy when used in combination with an LHRH-A for the treatment of patients with advanced prostate cancer. Bicalutamide 150-mg daily is considered an effective monotherapy for use in patients with locally advanced disease. Additional clinical trials are currently in progress to further evaluate Bicalutamide as a monotherapy for advanced prostate cancer and to assess its value as adjuvant or first-line therapy for early-stage prostate cancer. Prostate 34:61–72, 1998. © 1998 Wiley-Liss, Inc.

  • nical benefits of Bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma final report of a double blind randomized multicenter trial
    Urology, 1997
    Co-Authors: Paul F. Schellhammer, Roohollah Sharifi, Norman L Block, Mark S Soloway, Peter Venner, Lynn A Patterson, Michael F Sarosdy, Nicholas J Vogelzang, Julie Jones Schellenger, G J Kolvenbag
    Abstract:

    Abstract Objectives To compare the efficacy and tolerability of Bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer. Methods This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to Bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days). Results The median times to progression and death were 97 and 180 weeks for the Bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for Bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [Cl] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% Cl 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the Bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P Conclusions With a median follow-up time of 160 weeks, the combination of Bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with Bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

  • Worldwide activity and safety of Bicalutamide: a summary review.
    Urology, 1996
    Co-Authors: G J Kolvenbag, G R Blackledge
    Abstract:

    To evaluate Bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of Bicalutamide. To evaluate Bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of Bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of Bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of Bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P < 0.001) lower incidence of diarrhea and fewer withdrawals for adverse events among Bicalutamide-treated patients. With longer follow-up and a 34% mortality, survival was equivalent between groups. Dose-related effects of Bicalutamide on serum PSA concentrations were clearly demonstrated in the clinical trial program. With a total exposure of > 2800 patient-years, Bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, Bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

  • Worldwide activity and safety of Bicalutamide: a summary review.
    Urology, 1996
    Co-Authors: G J Kolvenbag, G R Blackledge
    Abstract:

    Abstract Objectives. To evaluate Bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of Bicalutamide. To evaluate Bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. Results. Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of Bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of Bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of Bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P 2800 patient-years, Bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. Conclusions. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, Bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

Kevin Carroll - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2004
    Co-Authors: Peter Iversen, Peter Klarskov, Janerik Johansson, Par Lodding, Olavi Lukkarinen, Per Lundmo, Teuvo L J Tammela, Ilker Tasdemir, Tom Morris, Kevin Carroll
    Abstract:

    ABSTRACTPurpose:: We evaluated the benefits of adding 150 mg Bicalutamide to standard care, that is radical prostatectomy, radiotherapy or watchful waiting (WW), in patients with localized or locally advanced prostate cancer.Materials and Methods:: A total of 1,218 men with T1–4, M0, any N prostate cancer were recruited from 62 Scandinavian centers and randomized 1:1 to 150 mg Bicalutamide or placebo plus standard care. Primary end points were progression-free survival (PFS) and overall survival.Results:: At a median 5.3-year followup patients with locally advanced disease had improved survival with Bicalutamide (HR 0.68, 95% CI 0.50 to 0.92), while those with localized disease had decreased survival with Bicalutamide (HR 1.47, 95% CI 1.06 to 2.03). Bicalutamide significantly improved PFS, decreasing the risk of disease progression by 43% compared with placebo (HR 0.57, 95% CI 0.48 to 0.68, p <0.0001). The rate of events was 35.4% for Bicalutamide and 46.2% for placebo. Patients with locally advanced dise...

  • Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer results from the second analysis of the early prostate cancer program at median followup of 5 4 years
    The Journal of Urology, 2004
    Co-Authors: Manfred P Wirth, Peter Iversen, Tom Morris, David G Mcleod, Kevin Carroll
    Abstract:

    ABSTRACTPurpose:: We evaluated the efficacy and tolerability of 150 mg Bicalutamide daily given in addition to standard care, in patients with localized or locally advanced prostate cancer.Materials and Methods:: The Bicalutamide Early Prostate Cancer program consists of 3 randomized, double blind, placebo controlled trials prospectively designed for combined analysis. A total of 8,113 men with T1b–T4, M0, any N (N0 in 1 trial) prostate cancer were randomized to Bicalutamide 150 mg/day (4,052) or placebo (4,061) in addition to standard care (radical prostatectomy, radiotherapy or watchful waiting). Primary end points were objective progression-free survival (PFS) and overall survival.Results:: At median 5.4 years of followup (21.6% progression events) Bicalutamide significantly improved PFS in the overall population. This result was driven by positive results in trials 24 and 25, with the North American trial (trial 23) showing no difference. Patients with locally advanced disease gained most benefit from...

  • casodex Bicalutamide 150 mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer results from two multicenter randomized trials at a median follow up of 4 years
    Urology, 1998
    Co-Authors: Peter Iversen, Kevin Carroll, C Tyrrell, Amir V Kaisary, John B Anderson, Luc Baert, T Tammela, Michael Chamberlain, Karen Gottingsmith, George Blackledge
    Abstract:

    Objectives. To compare the efficacy, tolerability, and quality of life benefits of Bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (MO) advanced prostate cancer. Methods. A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral Bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307). The design of these studies was similar to allow a pooled analysis. Results. In the combined survival analysis, at median follow-up of 202 and 205 weeks in studies 306 and 307, respectively, with 31% of the cases resulting in death, Bicalutamide 150-mg monotherapy was statistically equivalent to castration; the risk of death from any cause was 7% less with Bicalutamide than with castration (hazard ratio [HR] = 0.93). Data on time to treatment failure and objective progression could not be pooled, as results for these end points differed between the trials. In study 306, Bicalutamide 150-mg monotherapy increased time to objective progression (HR = 0.58; P = 0.033) and treatment failure (HR = 0.66; P = 0.074), whereas in study 307, time to progression (HR = 1.35; P = 0.0471) and treatment failure (HR = 1.24; P = 0.097) favored castration. Bicalutamide therapy showed significant advantages over castration for both sexual interest (P = 0.029) and physical capacity (P = 0.046). Bicalutamide 150-mg monotherapy was well tolerated. Conclusions. Bicalutamide 150-mg monotherapy provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostate cancer and confers statistically significant benefits over castration with respect to sexual interest and physical capacity.

G R Blackledge - One of the best experts on this subject based on the ideXlab platform.

  • Worldwide activity and safety of Bicalutamide: a summary review.
    Urology, 1996
    Co-Authors: G J Kolvenbag, G R Blackledge
    Abstract:

    To evaluate Bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of Bicalutamide. To evaluate Bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of Bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of Bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of Bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P < 0.001) lower incidence of diarrhea and fewer withdrawals for adverse events among Bicalutamide-treated patients. With longer follow-up and a 34% mortality, survival was equivalent between groups. Dose-related effects of Bicalutamide on serum PSA concentrations were clearly demonstrated in the clinical trial program. With a total exposure of > 2800 patient-years, Bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, Bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

  • Worldwide activity and safety of Bicalutamide: a summary review.
    Urology, 1996
    Co-Authors: G J Kolvenbag, G R Blackledge
    Abstract:

    Abstract Objectives. To evaluate Bicalutamide as a therapy in nearly 3000 patients with advanced prostate cancer and to determine the dose-ranging, pharmacodynamic, and pharmacokinetic properties of Bicalutamide. To evaluate Bicalutamide as a monotherapy or in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy. Results. Bicalutamide is a potent, nonsteroidal antiandrogen with a plasma half-life consistent with a once-daily schedule. Monotherapy trials with 50 mg of Bicalutamide established its intrinsic activity, as demonstrated by subjective and objective responses and decreases in PSA concentrations. In comparison with castration, 50 mg of Bicalutamide monotherapy was inferior with respect to survival. In a randomized, double-blind (for antiandrogen therapy) trial, with a median follow-up of 49 weeks, 50 mg of Bicalutamide plus an LHRH-A was superior (P = 0.005) to flutamide plus an LHRH-A in delaying time-to-treatment failure and was better tolerated, as was evident from a significantly (P 2800 patient-years, Bicalutamide has been shown to be a well-tolerated therapy with a low incidence of treatment-related withdrawals. Conclusions. Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, Bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.

Steven P. Balk - One of the best experts on this subject based on the ideXlab platform.

  • activity of androgen receptor antagonist Bicalutamide in prostate cancer cells is independent of ncor and smrt corepressors
    Cancer Research, 2007
    Co-Authors: Myles C Hodgson, Anthony N. Hollenberg, Inna Astapova, Steven P. Balk
    Abstract:

    The mechanisms by which androgen receptor (AR) antagonists inhibit AR activity, and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy, are not clear. Recent studies show that AR antagonists (including the clinically used drug Bicalutamide) can enhance AR recruitment of corepressor proteins [nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT)] and that loss of corepressors may enhance agonist activity and be a mechanism of antagonist failure. We first show that the agonist activities of weak androgens and an AR antagonist (cyproterone acetate) are still dependent on the AR NH2/COOH-terminal interaction and are enhanced by steroid receptor coactivator (SRC)-1, whereas the Bicalutamide-liganded AR did not undergo a detectable NH2/COOH-terminal interaction and was not coactivated by SRC-1. However, both the isolated AR NH2 terminus and the Bicalutamide-liganded AR could interact with the SRC-1 glutamine-rich domain that mediates AR NH2-terminal binding. To determine whether Bicalutamide agonist activity was being suppressed by NCoR recruitment, we used small interfering RNA to deplete NCoR in CV1 cells and both NCoR and SMRT in LNCaP prostate cancer cells. Depletion of these corepressors enhanced dihydrotestosterone-stimulated AR activity on a reporter gene and on the endogenous AR-regulated PSA gene in LNCaP cells but did not reveal any detectable Bicalutamide agonist activity. Taken together, these results indicate that Bicalutamide lacks agonist activity and functions as an AR antagonist due to ineffective recruitment of coactivator proteins and that enhanced coactivator recruitment, rather than loss of corepressors, may be a mechanism contributing to Bicalutamide resistance. [Cancer Res 2007;67(17):8388–95]

  • Bicalutamide Functions as an Androgen Receptor Antagonist by Assembly of a Transcriptionally Inactive Receptor
    The Journal of biological chemistry, 2002
    Co-Authors: David Masiello, Shinta Cheng, Glenn J. Bubley, Steven P. Balk
    Abstract:

    Prostate cancers (PCa) that relapse after androgen deprivation therapy invariably express high levels of androgen receptor (AR) and AR-regulated genes. Most do not respond to secondary hormonal therapies, including AR antagonists, and the mechanisms of AR activation in these clinically androgen-independent tumors are unclear. Bicalutamide, the most widely used AR antagonist, is a competitive antagonist shown previously to stabilize AR association with cytosolic heat shock protein complexes. This study found nuclear AR expression in Bicalutamide-treated androgen-independent PCa and found that Bicalutamide could stimulate AR nuclear translocation. Moreover, specific DNA binding by the Bicalutamide-liganded AR was demonstrated in vivo using a VP16-AR fusion protein and was confirmed by chromatin immunoprecipitation showing binding to the prostate-specific antigen enhancer in LNCaP PCa cells. Nonetheless, Bicalutamide could not stimulate interactions between the AR N and C termini or recruitment of steroid receptor coactivator proteins (SRC-1 or -2), although SRC transfection augmented AR activity in the presence of dihydrotestosterone and inhibitory concentrations of Bicalutamide. These results demonstrate that Bicalutamide stimulates the assembly of a transcriptionally inactive AR on DNA and support altered coactivator (or corepressor) expression as a mechanism of Bicalutamide-resistant androgen-independent PCa.