GTx-758 acts as a selectiveagonist of theestrogen receptor (ER), with a more than 10-fold preference for activation ofERα relative toERβ (EC50 = 2.1 and 27 nM, respectively).[1] The selectivity of GTx-758 for ERα over ERβ may confer reduced hypercoagulability and thrombophilia, asestradiol directly produces these effects inplatelets via activation of ERβ, which is the predominant isoform of the ER expressed in platelets.[1] It has been said that suppression of free testosterone levels by ERα activation-induced increase inhepaticsex hormone-binding globulin (SHBG) production is the primarymechanism of action of GTx-758 in the treatment of prostate cancer.[3]
In a phase II clinical trial of 1000 mg/day and 2000 mg/day GTx-758 versusleuprorelin for the treatment ofprostate cancer, GTx-758 suppressed total testosterone levels to a lower extent than leuprorelin but decreased free testosterone and PSA levels to a greater extent, suggesting superior effectiveness.[3] GTx-758 increased median SHBG levels by 495% (at 1000 mg/day) and 583% (at 2000 mg/day), which was considered to account for the greater relative decrease in levels of free testosterone.[3] There was a significantly lesser incidence ofestrogen deficiency-associatedside effects in the GTx-758 group.[3] For instance, there was a more than 4-fold lower incidence of hot flashes for GTx-758,C-terminal telopeptide (CTX) andbone specific alkaline phosphatase (BSAP) levels (markers ofbone turnover) increased in the leuprorelin group but decreased in the GTx-758 group (indicating a beneficial bone-sparing effect for GTx-758), andinsulin-like growth factor-1 levels (which are positively associated withinsulin resistance andmetabolic syndrome as well as progression of prostate cancer) increased in the leuprorelin group but decreased in the GTx-758 group.[3] Incidence of gynecomastia was not reported with GTx-758.[3] However, a higher incidence ofvenous thromboembolism (VTE) was observed with GTx-78 (4.1%) relative to leuprorelin (0.0%), and this led to early termination of the clinical trial.[3] The drug was said to be well tolerated aside from VTE.[3] Studies are underway with lower doses of GTx-758 as secondary hormonal therapy in prostate cancer to see if such doses minimize the incidence of VTE.[3]
In a subsequent phase II clinical trial of 150 mg/day and 250 mg/day GTx-758 in castration-resistant prostate cancer, GTx-758 increased median SHBG levels by 301% (with 250 mg/day), decreased free testosterone levels by median 44%, and decreased PSA levels.[5] Similarly to the prior phase II clinical trial, GTx-758 was regarded as well tolerated, and improved bone parameters, but there were still two possibly drug-related severe adverse effects (VTE andmyocardial infarction).[5]
^abcdefghiYu EY, Getzenberg RH, Coss CC, Gittelman MM, Keane T, Tutrone R, et al. (February 2015). "Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer".European Urology.67 (2):334–341.doi:10.1016/j.eururo.2014.06.011.PMID24968970.
^Jones A, Getzenberg RH, Dalton JT, Veverka KA (2011). "1448 Oral Administration of GTX-758, a Selective ERα Agonist, Induces Chemical Castration but Not Gynecomastia in Male Monkeys".The Journal of Urology.185 (4): e581.doi:10.1016/j.juro.2011.02.1361.ISSN0022-5347.
^abYu EY, Hancock ML, Babicz T, Tutrone RF, Ng C, Belkoff LH, et al. (2016).A phase II open-label trial of GTx-758 in men with castration-resistant prostate cancer: Final analysis of the primary endpoint. Genitourinary Cancers Symposium. American Society of Clinical Oncology (ASCO).doi:10.1200/jco.2016.34.2_suppl.185.
