toremifene and Prostatic-Neoplasms

Bone health is a significant concern in men with prostate cancer.. To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer.. Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017).. Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments.. Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome.. Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care.. Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated.. Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population.. Program in Evidence-Based Care.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Denosumab; Humans; Male; Osteoporosis; Osteoporotic Fractures; Prostatic Neoplasms; Toremifene

Toremifene is a triphenylethylene selective estrogen receptor modulator (SERM) that differs from tamoxifen in a single chloride ion addition on a side chain, resulting in a potentially more favorable toxicity profile.. This article reviews the pharmacokinetics of toremifene and its potential use for the treatment of osteoporosis. This article was based on articles found through a literature search containing the terms 'toremifene' and 'SERMs.'. Toremifene can be administered orally with an excellent bioavailability. The overall pharmacokinetic profile is remarkably similar to tamoxifen. Toremifene is highly metabolized in the liver and is eliminated primarily in the feces following enterohepatic circulation. Some of its metabolites retain biological activity. This SERM was approved by the FDA for the treatment of estrogen receptor-positive metastatic breast cancer and is under investigation for its potential skeletal benefits in men on androgen deprivation therapy. Despite the positive preclinical and clinical evidences for the prevention of bone loss and fractures, the chemopreventive effect on prostate cancer remains to be confirmed and an increased risk of venous thromboembolism was evidenced in a large Phase III trial. Thus, additional data are required to establish the full clinical profile of this compound and its potential advantages over antiresorptive agents commonly in use for the treatment of osteoporosis.

Topics: Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Liver; Male; Osteoporosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Thromboembolism; Toremifene

Osteoporosis is defined as a continuous loss of bone mineral density accompanied by an increased fracture risk in females and males. A fall of estrogen concentrations at the menopause and the consecutive rapid bone loss are an established pathogenic mechanism in female osteoporosis. Males do not have a menopause equivalent during which significant amounts of bone are lost. Several diseases, therapeutic strategies and nutritional deficiencies may also result in bone loss and reduced bone mineral density. Prostate cancer is the most common visceral malignancy in men. Suppression of endogenous androgen production as a therapeutic tool is commonly used in patients with non-metastatic prostate cancer and is associated with significant bone loss and an increased fracture risk. Androgen deprivation therapy is prescribed both for men with locally advanced or high-risk non-metastatic prostate cancer. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density and reduces fracture risk. Denosumab (a monoclonal antibody against RANK ligand) and toremifene (a selective estrogen receptor modulator) recently have been shown to be effective to reduce vertebral fractures in patients with non-metastatic prostate cancer receiving androgen-deprivation therapy. This overview focuses on cancer-treatment-induced bone loss in patients with non-metastatic prostate cancer.

Topics: Aged, 80 and over; Androgen Antagonists; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Denosumab; Diphosphonates; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Osteoclasts; Osteoporosis; Osteoporotic Fractures; Prostatic Neoplasms; Randomized Controlled Trials as Topic; RANK Ligand; Selective Estrogen Receptor Modulators; Spinal Fractures; Toremifene

In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer.

Topics: Androgen Antagonists; Antibodies, Monoclonal, Humanized; Bone Density; Bone Neoplasms; Clinical Trials as Topic; Clodronic Acid; Denosumab; Diphosphonates; Fractures, Spontaneous; Humans; Imidazoles; Male; Osteoclasts; Osteoporosis; Pamidronate; Prostatic Neoplasms; Quality of Life; Samarium; Toremifene; Zoledronic Acid

In men with metastatic or recurrent prostate cancer, androgen deprivation therapy (ADT) is the standard of care. Although effective in cancer control, ADT is associated with multiple adverse effects of which physicians and patients should be aware herein we review these side-effects and their potential management.. ADT reduces serum levels of testosterone and estrogen, resulting in changes in body composition, increased fracture risk, development of insulin resistance, and an unfavorable lipid profile. A number of studies have investigated the association of ADT with cardiovascular mortality; however, it is unclear whether such an association exists. Recently, two separate clinical trials have found that denosumab, a monoclonal antibody, and toremifene citrate, a selective estrogen receptor modulator, could be used to reduce the incidence of fracture in men on ADT.. By providing clinicians with a greater awareness of the literature on ADT, we may minimize the physical and psychological impact of its side-effects. Physicians should be aware of a recent statement by a multilateral advisory panel, stating that there is no indication for a cardiovascular evaluation before starting ADT. Finally, physicians should be informed of recent developments in the prevention of vertebral fractures in men on ADT.

Topics: Androgen Antagonists; Androgens; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Body Mass Index; Denosumab; Erectile Dysfunction; Gynecomastia; Humans; Insulin Resistance; Libido; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; RANK Ligand; Risk Assessment; Selective Estrogen Receptor Modulators; Testosterone; Toremifene; United States

Prostate cancer is among the most common causes of death from cancer in men, and accounts for 10% of all new male cancers worldwide. The diagnosis and treatment of prostate cancer place a substantial physical and emotional burden on patients and their families, and have considerable financial implications for healthcare providers and society. Given that the risk of prostate cancer continues to increase with age, the burden of the disease is likely to increase in line with population life-expectancy. Reducing the risk of prostate cancer has gained increasing coverage in recent years, with proof of principle shown in the Prostate Cancer Prevention Trial with the type 2 5alpha-reductase (5AR) inhibitor, finasteride. The long latency period, high disease prevalence, and significant associated morbidity and mortality make prostate cancer a suitable target for a risk-reduction approach. Several agents are under investigation for reducing the risk of prostate cancer, including selenium/vitamin E and selective oestrogen receptors modulators (e.g. toremifene). In addition, the Reduction by Dutasteride of Prostate Cancer Events trial, involving >8000 men, is evaluating the effect of the dual 5AR inhibitor, dutasteride, on the risk of developing prostate cancer. A successful risk-reduction strategy might decrease the incidence of the disease, as well as the anxiety, cost and morbidity associated with its diagnosis and treatment.

Topics: Aged; Azasteroids; Cholestenone 5 alpha-Reductase; Dutasteride; Enzyme Inhibitors; Finasteride; Humans; Male; Middle Aged; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Selenium; Toremifene; Vitamin E

With the completion of the Prostate Cancer Prevention Trial and the ongoing performance of several additional large-scale prostate cancer prevention trials interest in this intervention has increased. We review promising agents for prostate cancer prevention, clinical trial designs and how these agents may be used clinically.. We reviewed current and completed randomized chemoprevention trials for prostate cancer as well as the most promising agents for which evidence suggests that a decreased prostate cancer risk may result from their use.. Evidence suggests that lycopene, decreased dietary fat, antioxidants such as alpha-tocopherol and selenium, nonsteroidal anti-inflammatory drugs and selective estrogen receptor modulators such as toremifene and 5alpha-reductase inhibitors may prove useful for decreasing the risk of prostate cancer in a man. Ongoing studies are examining these agents in the 3 general scenarios of 1) general population studies (finasteride, alpha-tocopherol and selenium), 2) increased prostate specific antigen with negative biopsy (dutasteride) and 3) prostatic intraepithelial neoplasia (toremifene and selenium).. There are many agents that may decrease the risk of prostate cancer. It requires careful study of the agents in specific populations to determine whether risk is reduced, the magnitude of the risk reduction and the spectrum of side effects associated with the agent. Physicians caring for men entering the range of age of prostate cancer risk must be aware of these preventive opportunities.

Topics: 5-alpha Reductase Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Carotenoids; Dietary Fats; Humans; Lycopene; Male; Prostatic Neoplasms; Selenium; Tocopherols; Toremifene

Deregulation of the estrogen axis in humans prompts a series of tissue-specific events. In the breast and prostate, alterations in estrogen signalling lead to genotypic and phenotypic molecular alterations that result in dysplastic cellular appearance, deregulated cell growth and carcinoma. In bone, decreased estrogen leads to increased osteoclastogenesis and bone resorption, decreased bone mineral density and a significant fracture risk. Toremifene is a selective estrogen receptor modulator that exerts pharmacological activity in the breast, bone and prostate. An intense interest in developing this agent for prostate cancer chemoprevention is based on the reduction of premalignant and malignant prostate lesions in a transgenic model of prostate cancer. Biological and clinical activity was demonstrated in Phase II trials by the prevention of progression to prostate cancer in men with high-grade prostate intraepithelial neoplasia and through suppression of bone turnover biomarkers and increased bone mineral density in men on androgen deprivation therapy for prostate cancer.

Topics: Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Humans; Male; Prostatic Neoplasms; Selective Estrogen Receptor Modulators; Toremifene

Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Additional selective estrogen receptor modulators (SERMs) may prolong the durability of ADT, because androgen and estrogen signaling drive PC progression.. Men with treatment-naïve bone metastatic PC were randomly assigned in 1:1:1 fashion to receive ADT, toremifene 60 mg plus ADT (TOPADT), or raloxifene 60 mg plus ADT (RAPADT). The primary endpoint was the biochemical recurrence (BCR) rate, and secondary endpoints were changes of scores of the visual analogue scale (VAS) and the functional assessment of cancer therapy (FACT).. A total of 15 men, 5 each, were allocated to one of the three treatment arms. The basal serum prostate-specific antigen (PSA) level was 198 ng/mL (median, range; 30-8428). Bone metastases were graded as 1 (n = 11), 2 (n = 3), and 3 (n = 1) by the extent of disease. During the median follow-up period of 1370 days (range; 431-1983), BCR occurred in 3, 0 and 2 men in ADT, TOPADT and RAPADT group, respectively. The 5-year BCR-free rate was 30, 100 and 53 %, in ADT, TOPADT and RAPADT group, respectively (p = 0.04, ADT v.s. TOPADT, p = 0.48, ADT v.s. RAPADT and p = 0.12, TOPADT v.s. RAPADT). Scores of VAS improved in all groups and remained stable throughout the study. This analysis is limited as a preliminary result in a single center.. Toremifene with conventional ADT significantly improved the BCR rate in treatment-naïve bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy.. The protocol was registered at the University Hospital Medical Information Network ( UMIN ID;0,000,064,000 ) in Sep 25, 2011.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Bone Neoplasms; Estrogen Receptor alpha; Humans; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Toremifene

High-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial.. The GTx Protocol G300104 randomly assigned 1,590 men with biopsy-diagnosed HGPIN to receive toremifene or placebo for 3 years or until a diagnosis of PCa was made on prostate biopsy. As part of this phase III clinical trial, a central pathologist evaluated biopsies of patients with isolated HGPIN at baseline and 12, 24, and 36 months of follow-up. ERG immunohistochemistry was performed on biopsies from 461 patients and evaluated for protein overexpression.. ERG expression was detected in 11.1% of patients (51 of 461 patients) with isolated HGPIN. In the first year and during the 3-year clinical trial, 14.7% and 36.9% of 461 patients were diagnosed with PCa, respectively. Patients with ERG expression were more likely to develop PCa, with 27 (53%) of 51 ERG-positive and 143 (35%) of 410 ERG-negative patients experiencing progression to PCa (P = .014, Fisher's exact test). ERG expression was not associated with age, baseline PSA, Gleason score, or tumor volume.. This study underscores the necessity of more stringent follow-up for men with HGPIN that is also positive for ERG overexpression. Clinicians should consider molecular characterization of HGPIN as a means to improve risk stratification.

Topics: Aged; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Biopsy; Disease Progression; Gene Expression Regulation, Neoplastic; Gene Fusion; Humans; Male; Middle Aged; Neoplasm Grading; Oncogene Proteins, Fusion; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Toremifene; Up-Regulation

Androgen 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.. In 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.. The 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.. Toremifene 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.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Bone Density Conservation Agents; Double-Blind Method; Fractures, Bone; Humans; Male; Middle Aged; Prostatic Neoplasms; Risk; Toremifene

Prostate cancer (PCa) prevention remains an appealing strategy for the reduction of overtreatment and secondary adverse effects. We evaluated the efficacy of toremifene citrate 20 mg in PCa prevention among men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on biopsy.. One thousand five hundred ninety men with HGPIN, or HGPIN and atypia, and no PCa on prostate biopsy were randomly assigned 1:1 to receive toremifene citrate 20 mg or placebo in a 3-year phase III, double-blind, multicenter trial. Men underwent annual biopsy until cancer detection or study end. Efficacy analysis was performed in 1,467 men who underwent at least one on-study biopsy. Baseline risk factors were evaluated to determine influence on cancer detection.. Cancer was detected in 34.7% and 32.3% of men in the placebo and treatment groups, respectively, with no observed difference (P = .39, log-rank test) in PCa-free survival. The 3-year Kaplan-Meier PCa-free survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group. Exploration of baseline risk factors demonstrated no subset in which a risk reduction was observed. In the placebo group, 17.9%, 12.9%, and 13.6% of men at risk at the beginning of years 1, 2, and 3, respectively, were diagnosed with PCa.. Although toremifene 20 mg did not lower the PCa detection rate, men with isolated HGPIN have a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion in chemoprevention trials and require surveillance by periodic prostate biopsy.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Biopsy; Disease Progression; Disease-Free Survival; Double-Blind Method; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Population Surveillance; Prospective Studies; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Risk Assessment; Risk Factors; Selective Estrogen Receptor Modulators; Toremifene; Treatment Outcome

Whether 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.. A 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.. Compared 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.. In 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.

Topics: Absorptiometry, Photon; Aged; Androgen Antagonists; Black People; Bone Density; Bone Density Conservation Agents; Femur; Fractures, Bone; Hip; Humans; Incidence; Male; Middle Aged; Placebos; Prostatic Neoplasms; Spine; Survival Rate; Toremifene; United States; White People

Androgen 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.. Analysis 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.. Of 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.. White 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.

Topics: Aged; Androgen Antagonists; Bone Density Conservation Agents; Double-Blind Method; Humans; Male; Prostatic Neoplasms; Risk Factors; Spinal Fractures; Toremifene

Androgen 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.. This 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.. Compared 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.. Toremifene 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.

Topics: Aged; Androgen Antagonists; Bone Density Conservation Agents; Double-Blind Method; Humans; Male; Prospective Studies; Prostatic Neoplasms; Spinal Fractures; Toremifene

Androgen 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.. In 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.. The 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.. Toremifene 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.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Bone Density Conservation Agents; Double-Blind Method; Fractures, Bone; Humans; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors; Toremifene

We evaluated the effects of toremifene on bone mineral density, a surrogate for fracture risk, in men receiving androgen deprivation therapy for prostate cancer.. In an ongoing, multicenter, phase 3 fracture prevention study 1,392 men 50 years or older with prostate cancer receiving androgen deprivation therapy were randomized to 80 mg toremifene per day or placebo. Bone mineral density of the lumbar spine, total hip and femoral neck was assessed using dual energy x-ray absorptiometry. In this planned interim analysis of the first 197 subjects we compared bone mineral density changes from baseline to month 12 between the placebo and toremifene groups.. Compared with the placebo group men in the toremifene group had significant increases in bone mineral density at each evaluated skeletal site. Lumbar spine bone mineral density decreased 0.7% in the placebo group and increased 1.6% in the toremifene group (between group comparison p <0.001). Total hip bone mineral density decreased 1.3% in the placebo group and increased 0.7% in the toremifene group (p = 0.001). Femoral neck bone mineral density decreased 1.3% in the placebo group and increased 0.2% in the toremifene group (p = 0.009). Between group differences in the change in bone mineral density from baseline to month 12 were 2.3%, 2.0% and 1.5% for the lumbar spine, total hip and femoral neck, respectively.. Toremifene significantly increased hip and spine bone mineral density in men receiving androgen deprivation therapy for prostate cancer. The effect of toremifene on the fracture risk is being assessed in the ongoing randomized, controlled trial.

Topics: Aged; Bone Density; Bone Density Conservation Agents; Gonadotropin-Releasing Hormone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Toremifene

Androgen-deprivation therapy (ADT) is associated with greater risk of incident coronary heart disease and hospital admission for myocardial infarction; treatment-related increases in serum lipids may contribute to greater cardiovascular disease risk. We evaluated the effects of toremifene, a selective estrogen-receptor modulator, on fasting serum lipid levels in men receiving ADT for prostate cancer.. In an ongoing, multicenter, double-blind, placebo-controlled phase III fracture-prevention study, 1,389 men receiving ADT for prostate cancer were randomly assigned to receive toremifene (80 mg/d) or placebo. In this interim analysis of 188 patients, changes in fasting serum lipids from baseline to month 12 were compared between the placebo and toremifene groups.. Changes in serum lipids differed significantly between the groups. Mean (+/- SE) total cholesterol decreased by 1.0% +/- 1.7% from baseline to month 12 in the placebo group and decreased by 8.1% +/- 1.4% in the toremifene group (P = .001 for between group comparison). Low-density lipoprotein (LDL) cholesterol increased by 0.8% +/- 2.5% in the placebo group and decreased by 8.2% +/- 2.5% in the toremifene group (P = .003). In contrast, high-density lipoprotein (HDL) cholesterol decreased by 4.9% +/- 1.2% in the placebo group and increased by 0.5% +/- 2.2% in the toremifene group (P = .018). Triglycerides increased by 6.9% +/- 4.2% in the placebo group and decreased by 13.2% +/- 3.6% in the toremifene group (P = .003).. Toremifene significantly decreased total cholesterol, LDL cholesterol, and triglycerides, and increased HDL cholesterol in men receiving ADT for prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fractures, Malunited; Humans; Lipids; Male; Middle Aged; Osteoporosis; Prostatic Neoplasms; Toremifene; Triglycerides

A randomized, double-blind, dose finding, placebo controlled, parallel group clinical study was done to determine the incidence of prostate cancer in men with high grade prostatic intraepithelial neoplasia treated with toremifene.. A total of 514 patients with high grade prostatic intraepithelial neoplasia and no evidence of prostate cancer on screening biopsy were randomized to 20, 40 or 60 mg toremifene, or placebo daily for 12 months. Patients underwent re-biopsy at 6 and 12 months.. The number of evaluable patients, that is those with 1 on study biopsy who were compliant, was 447. The cumulative risk of prostate cancer was decreased in patients on 20 mg toremifene compared with placebo (24.4% vs 31.2%, p <0.05). The annualized rate of prevention was 6.8 cancers per 100 men treated. In patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was decreased by 48.2% with 20 mg toremifene compared with placebo (9.1% vs 17.4%, p <0.05). The 20 mg dose was most effective but cumulative and 12-month incidences of prostate cancer were lower for each toremifene dose vs placebo with a cumulative risk of 29.2% and 28.1%, and a 12-month incidence of 14.3% and 13.0% for 40 and 60 mg, respectively. Gleason scores were similar across treatments. The overall incidence of drug related and serious adverse events did not differ between any of the toremifene groups and the placebo group.. Toremifene decreased the incidence of prostate cancer by 1 year and had a tolerability profile comparable to that of placebo in a high risk population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Double-Blind Method; Humans; Male; Middle Aged; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Toremifene

Men with high-grade prostatic intraepithelial neoplasia (PIN) evident on prostate biopsy are at high risk for the eventual development of prostate cancer. The ability to reverse high-grade PIN may reduce the incidence or delay the development of prostate cancer. Toremifene (GTx-006, Acapodene trade mark ) is a selective estrogen receptor modulator that has been shown in the transgenic mouse model of prostate cancer to eliminate high-grade PIN and reduce the incidence of prostate cancer. This study was aimed at the evaluation of the safety and efficacy of toremifene in men diagnosed with high-grade PIN. This was an open-label, phase IIA clinical trial that enrolled 21 men (mean age, 64.7 years) with evidence of high-grade PIN on biopsy within 6 months of entry into the study. Eighteen of these men (86%) completed toremifene treatment (60 mg/day orally for 4 months) and then underwent follow-up prostate biopsy (8 cores) to determine high-grade PIN status. The effect of the drug on serum prostate-specific antigen (PSA), percentage of free PSA, testosterone, estradiol, and quality of life was also measured. After toremifene treatment, 72% of these 18 men (vs. 17.9% of historical controls) had no high-grade PIN on subsequent prostate biopsies. Mean PSA trended higher, and percentage of free PSA was increased. Quality of life was not significantly affected by treatment. There were 3 mild adverse events, and no serious adverse events. Toremifene appeared to reduce high-grade PIN in this small, exploratory trial. The drug was well tolerated. A double-blind, dose-finding, randomized, placebo-controlled phase IIB/III study is currently open to further study toremifene's activity against high-grade PIN and prostate cancer incidence.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Hormonal; Biopsy, Needle; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Quality of Life; Risk Assessment; Survival Analysis; Toremifene; Treatment Outcome

Toremifene has antiestrogenic and estrogenic properties in vitro and in vivo. In addition, it may have antiangiogenesis and antimicrotubule properties at higher doses. Studies have demonstrated the efficacy of this agent in the treatment of metastatic breast cancer. We performed a phase II trial of toremifene in patients with androgen-independent prostate cancer (AIPC). Patients with an increasing prostate-specific antigen level despite castrate testosterone levels and antiandrogen withdrawal were eligible. Patients could not have received prior salvage hormonal therapy or chemotherapy. Patients received toremifene at 300 mg/m2/d orally (maximum dose 640 mg/d). Fifteen patients were treated. Patients received treatment for a median of 13 weeks (range, 4-30 weeks). The median age was 72 years (range, 58-80 years). The median Eastern Cooperative Oncology Group performance status was 0. The treatment was well tolerated and toxicity was mild. Two patients had grade III hepatic toxicity; one had grade III hyperglycemia. There were no treatment-related deaths. No objective responses were demonstrated. In summary, toremifene is not effective therapy for AIPC at the dose and schedule evaluated in this trial.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Male; Middle Aged; Prostatic Neoplasms; Toremifene

Estrogen Receptor-α (ERα) expression is increased in prostate cancer and acts as an oncogene. We propose that blocking of estrogen hormone binding to ERα using the ERα blocker toremifene will reduce the tumorigenicity of prostate cancer, and nano-targeted delivery of toremifene will improve anticancer efficacy. We report the synthesis and use in an orthotopic mouse model of PLGA-PEG nanoparticles encapsulating toremifene and nanoparticles encapsulating toremifene that are also conjugated to anti-PSMA for targeted prostate tumor delivery.. Human prostate cancer cell line PC3M and a nude mouse model were used to test efficacy of nano-targeted and nano-encapsulated toremifene versus free toremifene on the growth and differentiation of tumor cells.. Treatment with free toremifene resulted in a significant reduction in growth of prostate tumor and proliferation, and its nano-targeting resulted in greater reduction of prostate tumor growth, greater toremifene tumor uptake, and enhanced tumor necrosis. Tumors from animals treated with nano-encapsulated toremifene conjugated with anti-PSMA showed about a 15-fold increase of toremifene compared to free toremifene.. Our data provide evidence that blocking ERα by toremifene and targeting prostate cancer tissues with anti-PSMA antibody on the nanoparticles' surface repressed the tumorigenicity of prostate cancer cells in this mouse model.

Topics: Animals; Antineoplastic Agents, Hormonal; Cell Differentiation; Cell Line, Tumor; Cell Survival; Drug Compounding; Drug Delivery Systems; Estrogen Receptor alpha; Humans; Male; Mice; Mice, Nude; Necrosis; Particle Size; Prostate-Specific Antigen; Prostatic Neoplasms; Tetrazolium Salts; Thiazoles; Tissue Distribution; Toremifene

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Humans; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Selective Estrogen Receptor Modulators; Toremifene

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Humans; Male; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Selective Estrogen Receptor Modulators; Toremifene

Topics: Androgen Antagonists; Fractures, Bone; Humans; Male; Prostatic Neoplasms; Risk Factors; Selective Estrogen Receptor Modulators; Toremifene

Topics: Bone Density Conservation Agents; Fractures, Bone; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms; Risk Factors; Toremifene

Topics: Androgen Antagonists; Bone Density; Bone Density Conservation Agents; Humans; Lipids; Male; Prostatic Neoplasms; Toremifene

Topics: Antineoplastic Agents, Hormonal; Chemoprevention; Cholestenone 5 alpha-Reductase; Enzyme Inhibitors; Finasteride; Humans; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Selective Estrogen Receptor Modulators; Toremifene

Although some anti-estrogens have been reported to inhibit the proliferation of prostate cancer cells, few studies on the mechanism by which they suppress the growth of prostate cancer have been reported. We investigated, for the first time, whether anti-estrogens modulate the transactivation activity of the androgen receptor (AR) in prostate cancer cells. In DU-145 cells transfected with AR, the transactivation activity of AR was inhibited by tamoxifen and toremifene, even in the presence of 10 nM of DHT. On the other hand, in LNCaP cells having an endogenous AR mutation at codon 877, the activity of AR was suppressed by faslodex in the presence of 10 nM DHT, whereas it was not inhibited by tamoxifen nor toremifene. In PC-3 cells, both the cell growth and the AR activity were remarkably inhibited by tamoxifen at 50 microM. Faslodex and toremifene inhibited AR activity to some extent, but they seemed to function as agonists at higher concentrations. In PC-3 cells, the inhibition of cell growth by flutamide, faslodex and toremifene was much less than their suppression of AR activity. We also demonstrated that a synthetic estrogen diethylstilbestrol and progesterone-related drugs such as chlormadinone acetate and allylestrenol dose-dependently inhibited the activity of AR in DU-145 and PC-3 cells. These results highlight the anti-androgenic aspect of anti-estrogens and estrogens in regard to the AR-mediated transcription of the relevant genes in prostate cancer.

Topics: Androgen Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Antagonists; Fulvestrant; Humans; Male; Mutation; Prostatic Neoplasms; Receptors, Androgen; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Transcriptional Activation

The chemopreventive efficacy of toremifene, an antiestrogen, was evaluated in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. TRAMP mice were segregated into three groups: (a) the low-dose toremifene group (6.6 mg/kg/day); (b) the high-dose toremifene group (33 mg/kg/day); and (c) the control placebo group. Efficacy of treatment was measured by the absence of palpable tumor. To extend these studies using more sensitive techniques, TRAMP mice were then treated with placebo, flutamide (an antiandrogen; 33 mg/kg/day), or toremifene (10 mg/kg/day). Animals from each treatment group were sacrificed at 7, 10, 15, 20, 25, and 30 weeks of age, and prostate tissues and seminal vesicles were harvested. Tissues from animals (n = 5) in each group were evaluated by wholemount dissections of genitourinary tracts, histology, immunohistochemistry, and Western blot analyses. Blood was pooled per group to measure estradiol and testosterone hormonal levels. Tumors formed at week 17 in the placebo group (n = 10), at week 21 in the high-dose toremifene group (n = 12), and at week 29 in the low-dose toremifene group (n = 12). This represents an increased tumor latency of up to 12 weeks. By 33 weeks, all animals in the placebo group had tumors compared with only 35% of the animals treated with toremifene. Although both flutamide and toremifene decreased tumor incidence compared with the placebo, toremifene was more effective than flutamide. High-grade prostatic intraepithelial neoplasia was observed in animals in the placebo group, but not in animals treated with toremifene. Moreover, toremifene-treated animals had prolonged survival compared with placebo-treated animals. By 33 weeks of age, 100% of the placebo-treated animals had developed palpable tumors and died, whereas 60% of the toremifene-treated animals were tumor free. T antigen levels in the prostate of toremifene-treated animals were similar to those of placebo-treated, age-matched animals. Whereas serum estradiol levels remained unchanged, the total and free testosterone levels were elevated in the toremifene-treated group. Toremifene treatment did not affect androgen receptor levels. Because toremifene prevented prostate cancer in a milieu of elevated blood free testosterone levels with no change in prostate androgen receptor expression, the mechanism of toremifene's chemopreventive activity may be through nonandrogenic pathways, such as estrogen receptor signaling.

Topics: Adenocarcinoma; Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents, Hormonal; Estradiol; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prostatic Neoplasms; Receptors, Androgen; Selective Estrogen Receptor Modulators; Testosterone; Toremifene

Topics: Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Humans; Male; Precancerous Conditions; Prostatic Neoplasms; Toremifene

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Estrogen Antagonists; Female; Humans; Lavandula; Male; Neoplasms; Oils, Volatile; Ovarian Neoplasms; Piperidines; Plant Oils; Plants, Medicinal; Prostatic Neoplasms; Raloxifene Hydrochloride; Retinoids; Tamoxifen; Toremifene