A biomarker trial of intermittent, low-dose bicalutamide in subjects at high risk for prostate cancer: Updated results.

A145

Background: Men with elevated PSA and no cancer at initial biopsies have an increased risk of developing prostate cancer (PC) and represent an important target for chemoprevention. Bicalutamide (Bic) is an androgen receptor antagonist currently employed in the treatment of PC with a prolonged half-life (~7 days). Bic treatment with standard doses is associated with significant side effects, including gynecomastia and breast pain. Purpose: To assess the activity and safety of an intermittent (weekly), low-dose Bic treatment in a phase I-II study in subjects with PSA > 4 ng/ml and no PC at initial biopsies, using changes in tissue morphology and biomarkers of proliferation and apoptosis, as well as in circulating biomarkers, as endpoints. Methods: Eligible subjects were sequentially and non-randomly assigned to either low-dose Bic (50 or 100 mg weekly) or no treatment for 6 months. Blood samples were obtained before treatment and after 3 and 6 months to assess changes in circulating biomarkers and sex hormones. A second biopsy was performed after 6 months to assess morphological and IHC changes induced by treatment. Results: Accrual was closed on July 2006, with 80 subjects enrolled (26 on 50 mg, 28 on 100 mg and 26 controls). Total and free PSA, as well as PAP, decreased significantly on Bic, without differences between doses. Testosterone (T), LH, E2 and SHBG levels increased on Bic, although only T changes on both doses and LH changes on Bic 100 mg were significantly different to controls (p<0.001). Changes in circulating hormones and biomarkers were evident after 3 months, and persisted through the 6th month of treatment. No change in circulating hormones or biomarkers was observed in the control group. An increasing proportion of subjects with HG-PIN at initial biopsy showed no PIN foci after 6 months of Bic 50 or 100 mg, 4/23 (17%) and 7/21 (33%), respectively, vs. 0/11 (0%) in the control group. Treatment was well tolerated, although breast pain was recorded in 0/19 (0%), 8/25 (32%) and 14/22 (64%), and gynecomastia in 0/19 (0%), 11/25 (44%) and 11/22 (50%) of subjects on no treatment, Bic 50 or 100 mg, respectively. Conclusions: Treatment with intermittent, low-dose bicalutamide of subjects at high risk of PC is associated with a favourable modulation of circulating biomarkers and T, which is of the same magnitude in each dose. Although E2 increase was not statistically significant, breast pain and gynecomastia developed in about half of treated subjects. A lower incidence of PIN was observed after 6 months of treatment with Bic, particularly on 100 mg week. Assessment of tissue biomarkers is underway.