Phase 2 Trial Of Gtx-758, An Estrogen Receptor Alpha Agonist, In Men With Castration-Resistant Prostate Cancer

An open-label phase 2 trial was performed to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to induce a >= 50% decrease in prostate-specific antigen (PSA) decline by day 90, modulate free testosterone and sex hormone -binding globulin (SHBG) levels, and affect estrogen deficiency -related adverse events in men with castratation-resistant prostate cancer. The 250 mg/d cohort met statistical significance for the PSA decline rate. SHBG levels were increased, there were beneficial effects on hot flashes, and there was a minimal rate of venous thromboembolic events.Introduction: Novel estrogen therapy has the potential to be efficacious, with a favorable adverse event profile, in castration-resistant prostate cancer (CRPC). We performed a phase 2 trial to assess the ability of GTx-758, an oral selective estrogen receptor alpha agonist, to result in a >= 50% PSA decline by day 90, modulate free testosterone and sex hormone-binding globulin (SHBG) levels, and affect estrogen deficiency adverse events. Patients and Methods: CRPC patients received GTx-758 in two dose cohorts, 125 and 250 mg/d. The primary endpoint was the proportion of subjects who experienced a >= 50% PSA decline by day 90. Secondary endpoints included changes in testosterone, SHBG, bone turnover markers, and hot flashes, as well as safety. Results: Four (10.5%) of 38 (95% CI, 2.9, 24.8; P = .120) and 10 (25.6%) of 39 patients (95% CI, 13.0, 42.1; P .001) in the GTx-758 125 and 250 mg/d cohorts, respectively, experienced >= 50% PSA decline. SHBG was increased, providing a mechanism for notable decreases in free testosterone. In the 250 mg/d cohort, 9 men presented with moderate to severe hot flashes, and after 12 weeks, 4 (44%) of 9 reported either mild or no hot flashes (P = .001). The rate of venous thromboembolic events was 0% and 5.1% in the 125 and 250 mg/d arms, respectively. Conclusion: GTx-758 has clinical activity for CRPC in a dose-dependent fashion. GTx-758 resulted in a reduction in hot flashes. On the basis of these findings, further clinical investigation of novel estrogen therapies is warranted. (C) 2020 Elsevier Inc. All rights reserved.