Androgens and Selective Androgen Receptor Modulators to Treat Functional Limitations Associated With Aging and Chronic Disease.

Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to treat functional limitations associated with aging and chronic diseases. This narrative review describes preclinical studies, mechanisms, and randomized trials of testosterone, other androgens, and nonsteroidal SARMs. Sex differences in muscle mass and strength and empiric use of anabolic steroids by athletes to increase muscularity and athletic performance provide supportive evidence of testosterone's anabolic effects.

Oral Sabizabulin for High-Risk, Hospitalized Adults with Covid-19: Interim Analysis.

BACKGROUND: Sabizabulin is an oral, novel microtubule disruptor that has dual antiviral and anti-inflammatory activities in preclinical models. METHODS: A randomized, multicenter placebo-controlled phase 3 clinical trial was conducted with hospitalized patients with moderate to severe Covid-19 who were at high risk for acute respiratory distress syndrome (ARDS) and death. Patients were randomly assigned (2:1) to 9 mg of oral sabizabulin or placebo daily (up to 21 days).

A Phase Ib/II Study of Sabizabulin, a Novel Oral Cytoskeleton Disruptor, in Men with Metastatic Castration-resistant Prostate Cancer with Progression on an Androgen Receptor-targeting Agent.

Purpose: Sabizabulin, an oral cytoskeleton disruptor, was tested in a phase Ib/II clinical study in men with metastatic castration-resistant prostate cancer (mCRPC).

Patients And Methods: The phase Ib portion utilized a 3+3 design with escalating daily oral doses of 4.5-81 mg and increasing schedule in 39 patients with mCRPC treated with one or more androgen receptor-targeting agents.

The effect of digital rectal exam on the 4Kscore for aggressive prostate cancer.

Background: The 4Kscore is a new commercially available blood-based diagnostic test which predicts risk for aggressive, clinically significant prostate cancer on prostate biopsy. The 4Kscore is currently restricted to patients who have not had a digital rectal exam (DRE) in the previous 96 h, owing to prior mixed data suggesting that prostate specific antigen (PSA) isoforms may increase by a statistically significant-if not necessarily clinically significant-amount shortly after DRE. Our primary objective was to determine if 4Kscore test results are affected by a preceding DRE.

The 4Kscore blood test accurately identifies men with aggressive prostate cancer prior to prostate biopsy with or without DRE information.

Introduction: The 4Kscore Test is a prebiopsy blood test that incorporates four prostate protein biomarkers along with patient clinical information to determine a man's risk for high-grade, aggressive (Gleason ≥7) prostate cancer. However, some men likely to benefit from the test may be seen in primary care settings where the digital rectal examination (DRE) information is not always obtained. In this study, we assessed the clinical validity of the 4Kscore Test when the DRE information was not included in the algorithm.

Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

Introduction: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.

Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer.

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.

Design, Setting, And Participants: Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot.

Selective androgen receptor modulators for the treatment of late onset male hypogonadism.

Several testosterone preparations are used in the treatment of hypogonadism in the ageing male. These therapies differ in their convenience, flexibility, regional availability and expense but share their pharmacokinetic basis of approval and dearth of long-term safety data. The brevity and relatively reduced cost of pharmacokinetic based registration trials provides little commercial incentive to develop improved novel therapies for the treatment of late onset male hypogonadism.

TMPRSS2:ERG gene fusion predicts subsequent detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia.

Purpose: 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.

Patients And Methods: 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.

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer.

Purpose Of Review: This review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer.

Recent Findings: Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient's quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia.

Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth.

Purpose: Castration-resistant prostate cancer (CRPC) may occur by several mechanisms including the upregulation of androgen receptor (AR), coactivators, and steroidogenic enzymes, including aldo keto reductase 1C3 (AKR1C3). AKR1C3 converts weaker 17-keto androgenic precursors to more potent 17-hydroxy androgens and is consistently the major upregulated gene in CRPC. The studies in the manuscript were undertaken to examine the role of AKR1C3 in AR function and CRPC.

Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial.

Background: Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.

Methods: We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months.

Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene.

Purpose: 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.

Patients And Methods: 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.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

Purpose: 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.

Materials And Methods: 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.

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.

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

Purpose: 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.

Materials And Methods: 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).

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.

BACKGROUND: Cachexia, 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.

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

Purpose: 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.

Factors associated with vertebral fractures in men treated with androgen deprivation therapy for prostate cancer.

Purpose: 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.

Materials And Methods: Analysis included men receiving androgen deprivation therapy for prostate cancer and enrolled in a phase III fracture prevention trial.

Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies.

Cancer cachexia is a complex metabolic condition characterized by loss of skeletal muscle. Common clinical manifestations include muscle wasting, anemia, reduced caloric intake, and altered immune function, which contribute to increased disability, fatigue, diminished quality of life, and reduced survival. The prevalence of cachexia and the impact of this disorder on the patient and family underscore the need for effective management strategies.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

Purpose: 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.

Materials And Methods: 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.

Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study.

Purpose: 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.

Patients And Methods: 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.

Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial.

Purpose: 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.

Materials And Methods: 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.

Toremifene--a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy.

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.

Evidence that transfer of functional p53 protein results in increased apoptosis in prostate cancer.

Purpose: INGN 201 (Ad-p53) is a replication-defective adenoviral vector that encodes a wild-type p53 gene driven by the cytomegalovirus promoter. INGN 201 has been shown to have antitumoral activity against human prostate cancer cell lines. This study was undertaken to determine the safety of INGN 201 in patients with locally advanced prostate cancer, to assess transgene expression, and to evaluate antitumoral activity.