title: 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.
  
  
  METHODS
  Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot.
  
  
  METHODS
  GTx-758 and leuprolide.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov identifier NCT01615120.
authors: University of Washington, Seattle, WA, USA. Electronic address: evanyu@u.washington.edu.
authors: Evan Y
authors: EY
authors: Yu
authors: GTx, Inc., Memphis, TN, USA.
authors: Robert H
authors: RH
authors: Getzenberg
authors: GTx, Inc., Memphis, TN, USA.
authors: Christopher C
authors: CC
authors: Coss
authors: South Florida Medical Research, Aventura, FL, USA.
authors: Marc M
authors: MM
authors: Gittelman
authors: Medical University of South Carolina, Charleston, SC, USA.
authors: Thomas
authors: T
authors: Keane
authors: Chesapeake Urology, Towson, MD, USA.
authors: Ronald
authors: R
authors: Tutrone
authors: Urologic Consultants of Southeastern Pennsylvania, Bala Cynwyd, PA, USA.
authors: Laurence
authors: L
authors: Belkoff
authors: Urology of Virginia, Virginia Beach, VA, USA.
authors: Robert
authors: R
authors: Given
authors: Associated Medical Professionals Urology, Syracuse, NY, USA.
authors: Joel
authors: J
authors: Bass
authors: San Bernardino Urological Associates, San Bernardino, CA, USA.
authors: Franklin
authors: F
authors: Chu
authors: Central Urology Group, Columbus, OH, USA.
authors: Michael
authors: M
authors: Gambla
authors: Genesis Healthcare Partners, San Diego, CA, USA.
authors: Franklin
authors: F
authors: Gaylis
authors: First Urology, Jeffersonville, IN, USA.
authors: James
authors: J
authors: Bailen
authors: GTx, Inc., Memphis, TN, USA.
authors: Michael L
authors: ML
authors: Hancock
authors: GTx, Inc., Memphis, TN, USA.
authors: Jordan
authors: J
authors: Smith
authors: GTx, Inc., Memphis, TN, USA.
authors: James T
authors: JT
authors: Dalton
authors: GTx, Inc., Memphis, TN, USA.
authors: Mitchell S
authors: MS
authors: Steiner
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D003692:Delayed-Action Preparations; D015536:Down-Regulation; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013739:Testosterone / Q000097:blood*; D016896:Treatment Outcome; D014481:United States
chemical_list: C000603456:3-fluoro-N-(4-fluorophenyl)-4-hydroxy-N-(4-hydroxyphenyl)benzamide; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D014408:Biomarkers, Tumor; D003692:Delayed-Action Preparations; D020845:Selective Estrogen Receptor Modulators; D013739:Testosterone; D016729:Leuprolide
keywords: Bone turnover; Estrogen receptor; Free testosterone; GTx-758; Leuprolide; Prostate cancer; Sex hormone-binding globulin