1448 ORAL ADMINISTRATION OF GTX-758, A SELECTIVE ERα AGONIST, INDUCES CHEMICAL CASTRATION BUT NOT GYNECOMASTIA IN MALE MONKEYS

INTRODUCTION AND OBJECTIVES: Gynecomastia is a psychologically distressing and sometimes painful estrogen-related side effect experienced by men on androgen deprivation therapy (ADT) for prostate cancer (PCa). Gynecomastia affects 40–80% of men on estrogen therapy (e.g. diethylstilbesterol; DES) and is of high incidence in men on antiandrogen monotherapy and in combination with a luteinizing hormone releasing hormone (LHRH) agonist. GTx-758 is a novel oral selective estrogen receptor alpha (ER ) agonist designed as first or second line therapy for advanced PCa. We evaluated and compared the effects of GTx-758 and DES on serum hormones, prostate specific antigen (PSA) and male breast development (gynecomastia) in male nonhuman primates. METHODS: Male monkeys (n 4–7 /group, 4 years of age), received daily gavage with vehicle, DES (0.05 or 2 mg/kg) or GTx-758 (1, 10, or 100 mg/kg) for a period of at least 56 days. Nipple diameter and prepuce were examined at necropsy. Mammary gland thickness was measured as the greatest thickness of glandular elements perpendicular to skin from histologic sections. Serum testosterone and PSA concentrations were determined by enzyme immunoassay. RESULTS: GTx-758 and DES reduced serum testosterone to castrate levels (i.e., 50 ng/dL) and GTx-758 markedly suppressed PSA. Treatment with DES produced signs of hyperestrogenicity, including a highly significant bilateral increase in nipple diameter as well as swollen prepuce in 4/4 (100%) monkeys within 22 days of treatment initiation with 2 mg/kg DES. Nipple diameter was 1.6 and 2 fold (P 0.01) higher for 0.05 and 2 mg/kg DES, respectively, compared to vehicle control. Mammary gland hypertrophy was also evident by a 5.3 to 5.8 fold increase in thickness for DES-treated monkeys compared to vehicle control. Monkeys treated with GTx-758 did not exhibit similar magnitudes of change in mammary or scrotal tissue. CONCLUSIONS: Oral administration of GTx-758 and DES significantly reduced serum testosterone to castrate levels and GTx758 lowered serum PSA. However, unlike DES, monkeys treated with GTx-758 did not exhibit significant signs of hyperestrogenicity including gynecomastia. Future phase II clinical trials are designed to demonstrate the efficacy and safety of GTx-758 and provide evidence that GTx-758 is an attractive option for first-line hormone therapy in advanced prostate cancer.