Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer.

Abstract

BACKGROUND:

A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course.

OBJECTIVE:

To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy.

DESIGN, SETTING, AND PARTICIPANTS:

Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot.

INTERVENTION:

GTx-758 and leuprolide.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

The primary end point was the proportion of patients achieving total testosterone ≤ 50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels.

RESULTS AND LIMITATIONS:

Of 159 randomized patients, leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000 mg [p<0.001], GTx-758 2000 mg [p=0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%).

CONCLUSIONS:

Although leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs.

PATIENT SUMMARY:

This paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events.

TRIAL REGISTRATION:

Clinicaltrials.gov identifier NCT01615120.

• Authors: Evan Y Yu, Robert H Getzenberg, Christopher C Coss, Marc M Gittelman, Thomas Keane, Ronald Tutrone, Laurence Belkoff, Robert Given, Joel Bass, Franklin Chu, Michael Gambla, Franklin Gaylis, James Bailen, Michael L Hancock, Jordan Smith, James T Dalton, Mitchell S Steiner
• Journal: European urology (Eur Urol) Vol. 67 Issue 2 Pg. 334-41 (Feb 2015) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 24968970 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Chemical References

• 3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide
• Antineoplastic Agents, Hormonal
• Benzamides
• Biomarkers, Tumor
• Delayed-Action Preparations
• Selective Estrogen Receptor Modulators
• Testosterone
• Leuprolide

Topics

• Administration, Oral
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (administration & dosage, adverse effects, therapeutic use)
• Benzamides (administration & dosage, adverse effects, therapeutic use)
• Biomarkers, Tumor (blood)
• Delayed-Action Preparations
• Down-Regulation
• Humans
• Leuprolide (administration & dosage, adverse effects, therapeutic use)
• Male
• Middle Aged
• Neoplasms, Hormone-Dependent (blood, drug therapy, pathology)
• Prospective Studies
• Prostatic Neoplasms (blood, drug therapy, pathology)
• Selective Estrogen Receptor Modulators (administration & dosage, adverse effects, therapeutic use)
• Testosterone (blood)
• Treatment Outcome
• United States