SES AUA 2013: Poster - GTx-758 is a potent oral ER-agonist that increases sex hormone binding globulin and decreases serum free testosterone in men with advanced prostate cancer

WILLIAMSBURG, VA USA (UroToday.com) - Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but is associated with severe side effects of estrogen deficiency.

GTx-758 is an oral, selective estrogen receptor alpha (ERα) agonist that suppresses free testosterone levels by increasing production of hepatic sex hormone binding globulin (SHBG). Herein we report the effects of GTx-758 on SHBG and free testosterone (T) levels in Phase II studies in healthy men and men with advanced prostate cancer.

aua sesMethods: Healthy male volunteers (n=60) received daily dosed of GTx-758 ranging from 609 to 1450 mg for up to 28 days. In Phase II studies, men with advanced prostate cancer (n=164) received 1 000 mg or 2 000 mg GTx-758 daily or Lupron Depot® (4 month), while men with castrate resistant prostate cancer (CRPC) (n=9) received 2000 mg GTx-758 daily. Serum concentration of SHBG and free T were determined at baseline and during treatment.

Results: Mean SHBG increases in healthy volunteers were 330, 379, 459 %, respectively, in men who received 609, 986, 1 450 mg after 28 days of dosing of GTx-758 daily as an oral solution. SHBG increases of 399 and 439 % were observed at 1 000 and 2 000 mg GTx-758 in men with advanced prostate cancer using a tablet formulation. In men with CRPC, serum PSA reductions of ≥50% were achieved in all men who were dosed for 30 days (n=4). Mean SHBG levels from the 7 men with at least one on study assessment were 429%. Trough concentrations of GTx-758 were significantly correlated to SHBG increase (p < 0.05). SHBG increased from day 28 to 90 in a time and dose dependent manner and were greater in studies using the tablet formulation. At day 28, serum free T was reduced by 59, 76 and 69% in men who received 609, 986, 1 450 mg GTx-758 solution, whereas 1 000 and 2 000 mg GTx-758 tablets resulted in 87 and 90% reduction in free T from baseline respectively. Prostate cancer patients receiving GTx-758 for 90 days realized SHBG increases approaching 600% and reductions in serum free T > 96%. Pharmacokinetic and pharmacodynamics modeling of the relationship indicated that significant increases in SHBG and reductions in free T can also be achieved with lower (125 to 500 mg) doses of GTx-758 tablet.

Conclusions: GTx-758 potently induces SHBG and reduces free T in a time and dose dependent manner. Trough concentrations actual and projected from Phase II GTx-758 pharmacokinetic data suggest that significant increases in serum SHBG and reductions in free T can be achieved with lower (125 to 500mg) doses of the GTx-758 that could demonstrate an acceptable efficacy and safety profile in men with CRPC.

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Presented by James Dalton, Christopher Coss, Robert Getzenberg, Mary Johnston, Michael Hancock, Ryan Taylor, and Mitchell Steiner at the 77th Annual Meeting of the Southeastern Section of the AUA - March 14 - 17, 2013 - Colonial Williamsburg Lodge - Williamsburg, VA USA

GTx, Inc., Memphis, TN USA

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