GTx-758 (tentative brand name Capesaris) is a synthetic nonsteroidal estrogen which was under development by GTx, Inc. for the treatment of advanced prostate cancer.[1] As of 2016, it had completed two phase II clinical trials.[2]
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Other names | Capesaris |
Routes of administration | By mouth |
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Formula | C19H13F2NO3 |
Molar mass | 341.314 g·mol−1 |
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Pharmacology
editPharmacodynamics
editGTx-758 acts as a selective agonist of the estrogen receptor (ER), with a more than 10-fold preference for activation of ER
Chemistry
editGTx-758 is a diphenyl benzamide and has a similar structure to stilbestrol derivatives like diethylstilbestrol and triphenylethylene derivatives like chlorotrianisene.[1]
Research
editPreclinical studies
editIn animal studies, GTx-758 reversibly suppresses testosterone concentrations to castrate levels, reduces prostate size and levels of prostate-specific antigen (PSA), but does not induce typical side effects associated with hyperestrogenism (or hypoestrogenism) including hot flashes, bone loss, thrombophilia, hypercoagulation, or increased body fat.[1] Unlike diethylstilbestrol, GTx-758 also does not induce gynecomastia in male monkeys, despite similarly suppressing testosterone levels to the castrate range (≤50 ng/dL) and markedly reducing PSA levels.[4]
Clinical studies
editIn a phase II clinical trial of 1000 mg/day and 2000 mg/day GTx-758 versus leuprorelin for the treatment of prostate 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 of estrogen deficiency-associated side 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) and bone specific alkaline phosphatase (BSAP) levels (markers of bone turnover) increased in the leuprorelin group but decreased in the GTx-758 group (indicating a beneficial bone-sparing effect for GTx-758), and insulin-like growth factor-1 levels (which are positively associated with insulin resistance and metabolic 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 of venous 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 and myocardial infarction).[5]
See also
editReferences
edit- ^ a b c d e Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, et al. (March 2012). "Preclinical characterization of a novel diphenyl benzamide selective ER
α agonist for hormone therapy in prostate cancer". Endocrinology. 153 (3): 1070–1081. doi:10.1210/en.2011-1608. PMID 22294742. - ^ "GTX 758". AdisInsight. Springer Nature Switzerland AG.
- ^ a b c d e f g h i Yu 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. PMID 24968970.
- ^ Jones A, Getzenberg RH, Dalton JT, Veverka KA (2011). "1448 Oral Administration of GTX-758, a Selective ER
α 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. ISSN 0022-5347. - ^ a b Yu 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.