Prostate Cancer

Selective Estrogen Receptor Alpha Agonist GTx-758 Decreases Testosterone with Reduced Side Effects of Androgen Deprivation Therapy in Men with Advanced Prostate Cancer

By: Evan Y. Yu a lowast , Robert H. Getzenberg b , Christopher C. Coss b , Marc M. Gittelman c , Thomas Keane d , Ronald Tutrone e , Laurence Belkoff f , Robert Given g , Joel Bass h , Franklin Chu i , Michael Gambla j , Franklin Gaylis k , James Bailen l , Michael L. Hancock b , Jordan Smith b , James T. Dalton b and Mitchell S. Steiner b

European Urology, Volume 67 Issue 2, February 2015, Pages 334-341

Published online: 01 February 2015

Keywords: Bone turnover, Estrogen receptor, Free testosterone, GTx-758, Leuprolide, Prostate cancer, Sex hormone-binding globulin

Abstract Full Text Full Text PDF (1,1 MB) Patient Summary



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


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.


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%).


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 identifier NCT01615120 .

Take Home Message

Estrogen receptor α agonist GTx-758 was compared with leuprolide as initial androgen deprivation therapy in men with rising prostate-specific antigen (PSA) after local therapy. Although leuprolide lowered serum total testosterone more rapidly and to a greater extent than either of the two doses of GTx-758 evaluated, greater sex hormone-binding globulin increases and free testosterone decreases may explain the significantly greater PSA declines observed in men treated with GTx-758. GTx-758 also lowered the risk of hot flashes and decreased bone turnover.

Keywords: Bone turnover, Estrogen receptor, Free testosterone, GTx-758, Leuprolide, Prostate cancer, Sex hormone-binding globulin.


a University of Washington, Seattle, WA, USA

b GTx, Inc., Memphis, TN, USA

c South Florida Medical Research, Aventura, FL, USA

d Medical University of South Carolina, Charleston, SC, USA

e Chesapeake Urology, Towson, MD, USA

f Urologic Consultants of Southeastern Pennsylvania, Bala Cynwyd, PA, USA

g Urology of Virginia, Virginia Beach, VA, USA

h Associated Medical Professionals Urology, Syracuse, NY, USA

i San Bernardino Urological Associates, San Bernardino, CA, USA

j Central Urology Group, Columbus, OH, USA

k Genesis Healthcare Partners, San Diego, CA, USA

l First Urology, Jeffersonville, IN, USA

lowast Corresponding author. University of Washington, Seattle Cancer Care Alliance, Department of Medicine, Division of Oncology, 825 Eastlake Avenue E, Box 358081, G4-800, Seattle, WA 98109, USA. Tel. +1 206 288 7595; Fax: +1 206 288 2042.

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