Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity

The non-steroidal antiandrogens flutamide (Eulexin(R)), nilutamide (Anandro n(R)) and bicalutamide (Casodex(R)) are widely used in the treatment of adv anced prostate cancer, particularly in combination with castration. The nat urally occurring ligand 5 alpha-DHT has higher binding affinity at the andr ogen receptor than the non-steroidal antiandrogens. Bicalutamide has an aff inity two to four times higher than 2-hydroxyflutamide, the active metaboli te of flutamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated th at bicalutamide also exhibits greater potency in reducing seminal vesicle a nd ventral prostate weights and inhibiting prostate tumour growth than flut amide. Although preclinical data can give an indication of the likely clini cal activity, clinical studies are required to determine effective, well-to lerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival benefits of flutamide plus a lutein ising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and fo r nilutamide plus orchiectomy over orchiectomy alone. Other studies have fa iled to show such survival benefits, including those comparing flutamide pl us orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH -A alone. In a direct comparative study, bicalutamide (50 mg, once daily) w as compared with flutamide (250 mg, three times daily), each in combination with an LHRH-A. Both therapies were well tolerated, although more patients could not tolerate flutamide therapy: 25 flutamide plus LHRH-A and 2 bical utamide plus LHRH-A patients withdrew from therapy due to diarrhoea. There were no statistically significant differences for time to progression or su rvival between the two antiandrogens. This clinical trial of bicalutamide c onfirms the prediction from preclinical studies that a 50 mg dose of bicalu tamide would be appropriate for use in patients with advanced prostate canc er, and demonstrates that this bicalutamide dose is clinically effective wh en administered as part of CAB.