GTx, Inc. this weekend presented results of the Capesaris™ (GTx-758) proof of concept pharmacokinetic-pharmacodynamic (PK/PD) clinical trial treating men with advanced prostate cancer, at the Annual Meeting of the Society of Urologic Oncology. Capesaris is a novel oral selective estrogen receptor alpha agonist which GTx is developing for first line treatment of advanced prostate cancer.

“As Capesaris advances from proof of concept into clinical trials in men with advanced prostate cancer, it is emerging as a promising drug candidate which represents a new approach to androgen deprivation therapy,” said Thomas Keane, M.D., Chairman and Professor of Urology at the Medical University of South Carolina. “Because of the mechanism of action through the estrogen receptor, Capesaris has the potential to suppress testosterone to castrate levels without previously documented problems of ADT such as bone loss and hot flashes.

In the Phase II PK/PD clinical trial, sixty healthy male volunteers (ages 18-40) were randomized to one of three Capesaris treatment arms, 600mg, 1000mg, or 1500mg. Subject compliance was determined by statistical comparison of trough Capesaris plasma concentrations. Subjects received oral Capesaris for 56 days or until they demonstrated castrate levels of testosterone (<50ng/dL) on two consecutive measures. The primary endpoint was serum total testosterone level. Key secondary endpoints included levels of serum free testosterone, the form of testosterone which prostate cancer cells utilize for growth, and sex hormone binding globulin (SHBG), a protein produced by the liver which strongly binds with testosterone and reduces serum free testosterone.Men receiving 1000mg and 1500mg of Capesaris achieved medical castration with a median time to castration of 17 days. Castration was not achieved in men treated with 600mg of Capesaris.1- In the 1500mg cohort, 91% of treatment compliant subjects (10 of 11) met the endpoint of castration with a total serum testosterone <50ng/dL. Six of 17 subjects who completed the study were found by statistical analysis of trough Capesaris levels to have been non-compliant with treatment and were not included in the analysis of castration.2- In the 1000mg dose group, 10 of 14 subjects (71%) who were deemed to be compliant and completed the study achieved castration. The mean serum free testosterone level in compliant subjects was 0.34 pg/mL (range 0.15–0.96 pg/mL).The mean levels of serum free testosterone range from 2.1 – 2.3 pg/mL in castration studies evaluating luteinizing hormone releasing hormone (LHRH) agonist treatment in young males (Schmidt et al, Arch Gen Psychiatry, 2004; 61:997-1004) and in men with prostate cancer (Smith, MR, Clin Cancer Res., 2007, 13(1):241-5). Treatment with Capesaris resulted in significant increases in SHBG, with a mean change from baseline of 446% and 596% for men in the 1000mg and 1500mg cohorts, respectively.Bone turnover markers osteocalcin and bone-specific alkaline phosphatase declined in men receiving 1000mg and 1500mg of Capesaris.Capesaris was generally well tolerated. No serious adverse events were reported in the study. The most common adverse events observed in the study were headache, upper respiratory tract infection, nipple pain, and nausea.A successful drug of this type could serve as either a first or second line treatment fore men with advanced prostate cancer.In the second quarter of 2011, GTx is planning to initiate a Phase IIb clinical trial evaluating Capesaris head to head compared to LHRH agonist treatment in men with advanced prostate cancer. About Capesaris™ (GTx-758)Currently, the standard of care for men with advanced prostate cancer is androgen deprivation therapy (ADT) achieved either surgically via bilateral orchiectomy or medically via injection of a luteinizing hormone releasing hormone (LHRH) agonist. Both of these ADT treatments often result in increased morbidity (bone loss and increased risk of clinical fragility fractures) and are associated with significant symptomatic side effects that can reduce treatment compliance and negatively effects the quality of life (QOL).Capesaris, like the other second line, but unapproved treatments, has the potential to achieve medical castration by feedback inhibition of the pituitary and hypothalamus without bone loss and hot flashes.In a prior phase I trial, Capesaris was well tolerated and demonstrated a pharmacokinetic profile compatible with daily oral dosing. Of course, this study is only a phase II study, but it does show promise. I am concerned that the definition used for castration was <50ng/dL. I believe that this is not a low enough number, the best goal for castration should be <20ng/dL. The report did not provide the actual numbers achieved, so we do not know if the experimental endpoint of <50ng/dL meant that the men were <49ng/dL or if they were actually under <20ng/dL.Joel T Nowak, M.A., M.S.W.