GTx-758, ERa Agonist, Reduces Both Serum Free testosterone(T) and Serum PSA in Men With Advanced and Castrate Resistant Prostate Cancer GTx-758, ERa Agonist, Reduces Both Serum Free Testosterone(T) and Serum PSA in Men With Advanced and Castrate Resistant Prostate Cancer -- Coss et al. 34 (3): SAT-319 -- Endocrine Reviews Introduction: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer. Primary ADT with LHRH analogs lowers serum total testosterone (T) by reducing testicular androgen production, thereby lowering serum total and serum free T. Estrogen-based ADT induces sex hormone binding globulin (SHBG) expression resulting in proportionally greater reductions in serum free T. Primary ADT patients achieving lower serum T levels, and men with CRPC undergoing secondary hormonal therapy to further reduce T, experience better prostate cancer outcomes. Objectives: Herein we compare the effects GTx-758 (an oral, selective estrogen receptor alpha (ER?) agonist) versus leuprolide on total T, free (unbound) serum T, SHBG and PSA levels in men with advanced prostate cancer. Methods: In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot® (4 month), while men with CRPC (n=7) received 2000 mg GTx-758 daily while on ADT. Serum concentrations of total T, free T, PSA and SHBG were determined at baseline and during treatment. Results: The ADT naïve ITT population receiving GTx-758 demonstrated a mean reduction in serum total T from baseline of 54±52 and 72±43% for the 1000 and 2000 mg doses, respectively, compared to 93±2.8% reduction in the Lupron treated arm at Day 21. However, mean PSA reductions from baseline at Day 21 were 55±47 and 60±32% for the 1000 and 2000 mg doses of GTx-758, respectively, compared to 38±24% in Lupron treated patients. GTx-758 treatment resulted in 55 and 51% greater reduction in serum free T per unit reduction in serum total T relative to Lupron in the 1000 mg and 2000 mg arms, respectively, at Day 21. Reductions in serum free T coincided with mean increases in SHBG of 399±186 and 439±165% for 1000 mg and 2000 mg GTx-758 groups, respectively, compared to 5±14% in Lupron treated patients at Day 28. SHBG inductions were highly correlated with reductions in %Free T([free T/total T]X100) in both ADT naïve and CRPC prostate cancer patients (p<0.001). Conclusions: Although GTx-758 and LHRH ADT, both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, SHBG induction rapidly reduced %free T to a greater degree in only the GTx-758 treated patients. GTx-758 therapy also demonstrated efficacy in men with CRPC, with similar reductions in %free T and PSA observed. The ability of GTx-758 to reduce free T demonstrates a unique and effective mechanism to treat men with advanced prostate cancer and CRPC.