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

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 (M0) 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 ≈ 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.

Bicalutamide plus Anastrozole for the Treatment of Gonadotropin-Independent Precocious Puberty in Boys with Testotoxicosis: A Phase II, Open-Label Pilot Study (BATT)

“…The safety and tolerability results obtained in this study are consistent with those expected in a pediatric population of boys with testotoxicosis and with the known safety profiles of bicalutamide and anastrozole [14][15][16][17][18][19][20][21] . For example, the most common treatment-related AE, gynecomastia, is both a feature of the disease as well as a consequence of bicalutamide treatment.…”

“…Since this early study, more potent and specific non-steroidal antiandrogens, such as bicalutamide (Casodex™), and aromatase inhibitors, such as anastrozole (Arimidex™), have become available for the treatment of hormone-sensitive cancers and a number of studies have confirmed the efficacy and favorable tolerability profile of bicalutamide [14][15][16][17] and anastrozole [18][19][20][21] in adults. The most common adverse events (AEs) reported with bicalutamide are gynecomastia and breast pain, while anastrozole is associated with an increased risk of bone fracture compared with tamoxifen during long-term use in post-menopausal women.…”

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

“…This study demonstrates that Hsp90 inhibitors act in synergy with AR antagonists to enhance AR blockade and reduce survival of prostate cancer cells while also minimizing known mechanisms of resistance. Importantly, these effects were demonstrated using doses of each agent that individually were not effective and are both clinically achievable and tolerable (Kelly et al 2003, Tyrrell et al 2006, Solit et al 2007.…”

Contemporary Role of Androgen Deprivation Therapy for Prostate Cancer

“…In nonmetastatic patients, reported results are not considered sufficiently mature at this time, whereas a significant survival advantage for castration was seen in the M1 subgroup [71]. More recently, Tyrrell et al [72] studied higher-dose bicalutamide (300, 450, and 600 mg) with regard to tolerability, pharmacokinetics, and clinical efficacy in M0 and M1 patients. Although survival resulted comparable to that for men receiving castration, larger series of patients are needed to confirm these data.…”