Ronald A. Morton

The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial

BackgroundCachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen receptor modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.MethodsA 12-week double-blind, placebo-controlled phase II clinical trial was conducted to evaluate GTx-024 in 120 healthy elderly men (>60xa0years of age) and postmenopausal women. The primary endpoint was total lean body mass assessed by dual energy X-ray absorptiometry, and secondary endpoints included physical function, body weight, insulin resistance, and safety.ResultsGTx-024 treatment resulted in dose-dependent increases in total lean body mass that were statistically significant (Pu2009<u20090.001, 3xa0mg vs. placebo) and clinically meaningful. There were also significant improvements in physical function (Pu2009=u20090.013, 3xa0mg vs. placebo) and insulin resistance (Pu2009=u20090.013, 3xa0mg vs. placebo). The incidence of adverse events was similar between treatment groups.ConclusionGTx-024 showed a dose-dependent improvement in total lean body mass and physical function and was well tolerated. GTx-024 may be useful in the prevention and/or treatment of muscle wasting associated with cancer and other chronic diseases.

Toremifene to Reduce Fracture Risk in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSEnAndrogen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period.nnnMATERIALS AND METHODSnIn this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes.nnnRESULTSnThe 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups.nnnCONCLUSIONSnToremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Toremifene decreases vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer.

PURPOSEnAndrogen deprivation therapy is associated with an increased fracture risk. In a recent phase III trial toremifene significantly decreased vertebral fractures in men on androgen deprivation therapy. Similar to other selective estrogen receptor modulators, toremifene was associated with an increase in venous thromboembolic events with the greatest risk in men 80 years old or older. In this post hoc analysis we evaluated the efficacy and safety of toremifene in men younger than 80 years.nnnMATERIALS AND METHODSnThis analysis included 847 men younger than 80 years, of whom 430 received toremifene 80 mg by mouth daily and 417 received placebo for up to 24 months. The primary end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and safety.nnnRESULTSnCompared with placebo, toremifene decreased the relative risk of new vertebral fractures by 79.5% (95% CI 29.8-94.0, p <0.005). The new vertebral fracture incidence was 1.0% for toremifene and 4.8% for placebo (absolute risk reduction 3.8%). Compared with placebo, toremifene significantly decreased the incidence of nontraumatic fracture or greater than 7% bone loss by 24 months (p <0.0001). Toremifene also significantly increased bone mineral density at all measured sites (all comparisons p <0.001). The incidence of venous thromboembolic events was similar in the toremifene and placebo groups (2.1% and 1.0%, respectively, p = 0.26). The rates of other adverse events were also similar between the groups.nnnCONCLUSIONSnToremifene significantly decreased new vertebral fractures in men younger than 80 years receiving androgen deprivation therapy for prostate cancer. The risk of venous thromboembolic events was lower than in the overall study population, suggesting an improved risk-benefit profile in younger men.

Factors Associated With Vertebral Fractures in Men Treated With Androgen Deprivation Therapy for Prostate Cancer

PURPOSEnAndrogen deprivation therapy for prostate cancer causes accelerated loss of bone mineral density and is associated with increased fracture risk. We evaluated risk factors associated with vertebral fractures among men enrolled in a fracture prevention trial.nnnMATERIALS AND METHODSnAnalysis included men receiving androgen deprivation therapy for prostate cancer and enrolled in a phase III fracture prevention trial. All men were 70 years old or older or had a low bone mineral density (T-score less than -1.5 for the lumbar spine or total hip). We analyzed demographic and laboratory characteristics of men with and those without vertebral fractures at study entry.nnnRESULTSnOf the 1,244 subjects 162 (13.0%) had a vertebral fracture at baseline. The 2 factors significantly associated with vertebral fractures were white race (p=0.028 compared with nonwhite race) and osteoporosis (p=0.002 for osteoporosis at any site, p=0.053 for osteoporosis at the spine, p=0.002 for osteoporosis at the hip). Lower bone mineral density was also significantly associated with vertebral fractures when analyzed as a continuous variable. Factors not associated with vertebral fractures included age, country of residence, androgen deprivation therapy duration at baseline, androgen deprivation therapy mode, body mass index, testosterone, estradiol, C-telopeptide, bone specific alkaline phosphatase and osteocalcin. Results were similar in analyses limited to men 70 years old or older.nnnCONCLUSIONSnWhite race and low bone mineral density were significantly associated with vertebral fractures in this study of men treated with androgen deprivation for prostate cancer. These observations should inform the assessment and management of fracture risk among such men.

Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer

PURPOSEnWhether race influences bone loss and fracture risk during androgen deprivation therapy for prostate cancer is unknown. Using data from a prospective clinical trial we compared bone mineral density and fracture between African-American and Caucasian men receiving androgen deprivation therapy.nnnMATERIALS AND METHODSnA total of 516 subjects were in the placebo group of a 2-year randomized placebo controlled fracture prevention trial, and were African-American (68) or Caucasian (448). We compared baseline characteristics, changes in bone mineral density and rates of new fractures between races.nnnRESULTSnCompared to Caucasian men, African-American men had higher baseline hip bone mineral density (mean ± SD 0.98 ± 0.15 vs 0.91 ± 0.15 gm/m(2), p = 0.001) and similar spine bone mineral density (1.09 ± 0.22 vs 1.11 ± 0.22, p = 0.51). There was no difference in prevalent vertebral fractures between African-American and Caucasian men (7.4% vs 15.0%, p = 0.13). The percentage change in hip bone mineral density at 2 years was similar between African-American and Caucasian men (mean ± SE -2.21% ± 0.59% vs -2.54% ± 0.26%, p = 0.65). Changes in bone mineral density of the lumbar spine were also similar between African-American and Caucasian men (-1.74% ± 0.69% vs -1.30% ± 0.33%, p = 0.64). No new vertebral fractures were reported in African-American men but 2 fractures were reported in Caucasian men.nnnCONCLUSIONSnIn a clinical trial African-American men receiving androgen deprivation therapy for prostate cancer have a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. Despite a lower baseline risk of osteoporosis and fracture, African-American men experience a decrease in bone mineral density similar to that of Caucasian men.

Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

Effect of toremifene on fracture risk in men younger than age 80 on androgen-deprivation therapy.

4676 Background: The use of androgen deprivation therapy (ADT) in prostate cancer is associated with increased fracture risk. Previously we demonstrated in a phase III trial that toremifene, a selective estrogen receptor modulator (SERM), significantly decreased fracture incidence in men receiving ADT. Similar to other SERMs, there was an increase in venous thromboembolic events. This risk appeared to stratify to men ≥80 years of age. VTEs occurred in 1.5% and 2.5% of men <80, ≥80 respectively. To identify a patient population with the greatest benefit/risk profile we assessed the effect of toremifene in men <80 years. Methods: In this analysis of men <80 years of age receiving ADT for prostate cancer, 430 men received toremifene 80 mg and 417 received placebo (orally daily). All subjects were on ADT for ≥ 6 months, had a serum PSA ≤4 ng/mL, were ≥70 years of age or were at or below WHO thresholds for spine or hip (BMD). The primary endpoint was new vertebral fractures. Secondary endpoints included fragil...