C.J. Tyrrell

A Randomised Comparison of ‘Casodex’TM (Bicalutamide) 150 mg Monotherapy versus Castration in the Treatment of Metastatic and Locally Advanced Prostate Cancer

Objectives: To evaluate the efficacy and tolerability of ‘Casodex’TM monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer. Methods: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M₀) were recruited into one of two identical, multicentre, randomsied studies to compare ‘Casodex’ 150 mg/day with castration. The protocols allowed for combined analysis. Results: At a median follow-up period of approximately 100 weeks for both studies, ‘Casodex’ 150 mg was found to be less effective than castration in patients with metastatic disease (M1) at entry (hazard ratio of 1.30 for time to death) with a difference in median survival of 6 weeks. In symptomatic M1 patients, ‘Casodex’ was associated with a statistically significant improvement in subjective response (70%) compared with castration (58%). Analysis of a validated quality-of-life questionnaire proved an advantage for ‘Casodex’ in sexual interest and physical capacity. ‘Casodex’ had a substantially lower incidence of hot flushes compared to castration (6–13% compared with 39–44%) and the most commonly reported adverse events were those expected for a potent antiandrogen. However, in patients with M₀ disease at entry, the data are still immature with only 13% of M₀ patients having died. An initial analysis of this immature data has suggested that the results in these patients may be different to those obtained in patients with M1 disease. A further survival analysis in patients with M₀ disease is therefore planned when the data are more mature. Conclusions: ‘Casodex’ 150 mg is less effective than castration in patients with M1 disease. However, ‘Casodex’ has shown a benefit in terms of quality of life and subjective response when compared to castration and has an acceptable tolerability profile. Thus ‘Casodex’ 150 mg monotherapy is an option for patients with M1 prostate cancer for whom surgical or medical castration is not indicated or is not acceptable.

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

PURPOSE We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. MATERIALS AND METHODS This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. RESULTS Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. CONCLUSIONS Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

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

OBJECTIVES To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (M0) 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.

A Multicenter Randomized Trial Comparing the Luteinizing Hormone-Releasing Hormone Analogue Goserelin Acetate Alone and with Flutamide in the Treatment of Advanced Prostate Cancer

AbstractA prospective randomized trial was conducted to compare the effects of the nonsteroidal antiandrogen flutamide (250mg. 3 times daily) plus the luteinizing hormone-releasing hormone analogue goserelin acetate (Zoladex) (3.6mg. subcutaneous depot injection every 28 days) with goserelin acetate alone in advanced prostatic carcinoma. A total of 571 eligible patients, of whom 57% had distant metastases, showed no difference in subjective or objective response rates, interval to progression, treatment failure or survival after a median followup of 2 years. In the combination group more patients had an early decrease in elevated levels of tumor markers and the small number of patients with an increase in signs and symptoms within the first 4 weeks showed a significant decrease. However, increased gastrointestinal and hepatic toxicity in the combination group resulted in 44 patients being withdrawn from the trial. These results indicate that the combination of goserelin acetate with flutamide provides no ...

A Randomised Comparison of Monotherapy with Casodex 50 mg Daily and Castration in the Treatment of Metastatic Prostate Carcinoma

Casodex (Bicalutamide, ICI 176,334) is a potent, non-steroidal, selective anti-androgen with a long half-life allowing once-daily oral administration. In this randomised, open, multicentre study, Casodex 50 mg monotherapy was compared with castration (medical, using goserelin acetate, [Zoladex], or surgical) in 245 patients with advanced prostate cancer. Primary end-points were time to treatment failure, time to objective progression and survival. Subjective responses, quality of life and tolerability were also evaluated. There was no significant difference between the groups in terms of objective progression or subjective responses. Treatment failed in 59 of 119 patients (50%) randomised to Casodex and in 61 of 126 patients (48%) randomised to castration (no statistically significant difference). An updated analysis showed that survival was similar in the two groups. Casodex was well tolerated with a low incidence of diarrhoea and sexual dysfunction. On the basis of this study, Casodex monotherapy is an effective alternative to castration in the treatment of metastatic prostate cancer.

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

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 (M0) or metastatic (M1) prostate cancer, with efficacy as a secondary endpoint.

Adjuvant and neoadjuvant hormonal therapy for prostate cancer

Many men with early stage prostate cancer suffer relapse and/or die of their disease despite potentially curative surgery or radiotherapy. Early hormonal therapies are being combined with these local therapies, with the aim of facilitating local control and improving survival. In the surgical setting, neoadjuvant hormonal therapy reduces the rate of positive margins and extracapsular penetration, but most studies have failed to demonstrate an advantage with respect to biochemical progression. Further studies are needed to clarify the role of adjuvant therapy in surgical patients. In the radiotherapy setting, neoadjuvant hormonal therapy improves local control, although survival data is not available, and can be considered for stage T2b disease or higher. Adjuvant luteinizing hormone-releasing hormone (LH-RH) agonists improve both local control and survival after radiotherapy and should be offered to all patients. Currently, the LH-RH agonists are the drugs of choice for adjuvant therapy, whereas combined androgen blockade has generally been used as neoadjuvant therapy. Monotherapy with a nonsteroidal antiandrogen has considerable potential in both settings. Areas for future studies include appropriate endpoints for clinical studies, comparative drug efficacy and the effect of treatment on quality of life.

Comparison of an LH–RH Analogue (Goeserelin Acetate, ‘Zoladex’) with Combined Androgen Blockade in Advanced Prostate Cancer: Final Survival Results of an International Multicentre Randomized–Trial

Objective: The aim of this study was to compare the effects of the nonsteroidal antiandrogen flutamide plus the LH–RH analogue goserelin acetate (combined androgen blockade [CAB]) with goserelin acetate alone in patients with advanced prostate cancer. The original analyses at 25 and 56 months of follow–up have been reported previously, and here we report the final survival analysis after 10 years of follow–up.Methods: 589 patients with advanced prostate cancer (55% with metastatic [M1] and 45% with locally advanced [M0] disease) were randomized to receive goserelin acetate 3.6 mg either alone or in combination with flutamide (250 mg three times daily).Results: A total of 583 patients were included in the analysis. There was a small, but nonsignificant, benefit for CAB compared with goserelin acetate alone in all patients with respect to survival (hazard ratio 0.88, 95% CI 0.73, 1.06). Subgroup analysis of M0 and M1 patients showed similar results (M0: hazard ratio 0.92, 95% CI 0.68, 1.25; M1: hazard ratio 0.85, 95% CI 0.66, 1.08). The treatment effect was not significantly different for M0 and M1 patients (p = 0.685).Conclusions: In this large randomized trial containing significant numbers of M0 patients, after 10 years there was a small but nonsignificant benefit for CAB over castration alone.