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Journal of Clinical Oncology : Official... Nov 2019Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).
METHODS
ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival.
RESULTS
As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; < .001; median not reached 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT ( < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events.
CONCLUSION
Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.
Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostatic Neoplasms
PubMed: 31329516
DOI: 10.1200/JCO.19.00799 -
American Society of Clinical Oncology... Apr 2022Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including... (Review)
Review
Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy (ADT), and clinical trials. This article reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer. First, radiation therapy, including selection of field, dose, and use of concurrent antiandrogen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Finally, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.
Topics: Androgen Antagonists; Combined Modality Therapy; Humans; Male; Neoplasm Recurrence, Local; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Salvage Therapy
PubMed: 35503984
DOI: 10.1200/EDBK_351033 -
The Lancet. Diabetes & Endocrinology Apr 2017Transgender women experience lifelong gender dysphoria due to a gender assignment at birth that is incongruent with their gender identity. They often seek hormone... (Review)
Review
Transgender women experience lifelong gender dysphoria due to a gender assignment at birth that is incongruent with their gender identity. They often seek hormone therapy, with or without surgery, to improve their gender dysphoria and to better align their physical and psychological features with a more feminine gender role. Some of the desired physical changes from oestrogen and anti-androgen therapy include decreased body and facial hair, decreased muscle mass, breast growth, and redistribution of fat. Overall the risks of treatment are low, but include thromboembolism, the risk of which depends on the dose and route of oestrogen administration. Other associated conditions commonly seen in transgender women include increased risks of depression and osteoporosis. The risk of hormone-sensitive cancer seems to be low in transgender women, with no increased risk of breast cancer compared with women and no increase in prostate cancer when compared with men. The evidence base for the care of transgender women is limited by the paucity of high-quality research, and long-term longitudinal studies are needed to inform future guidelines.
Topics: Androgen Antagonists; Estrogens; Female; Hormone Replacement Therapy; Humans; Male; Transgender Persons; Transsexualism; Treatment Outcome
PubMed: 27916515
DOI: 10.1016/S2213-8587(16)30319-9 -
Journal of the American Academy of... Jul 2019Hidradenitis suppurativa is a severe and debilitating dermatologic disease. Clinical management is challenging and consists of both medical and surgical approaches,... (Review)
Review
North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part II: Topical, intralesional, and systemic medical management.
Hidradenitis suppurativa is a severe and debilitating dermatologic disease. Clinical management is challenging and consists of both medical and surgical approaches, which must often be combined for best outcomes. Therapeutic approaches have evolved rapidly in the last decade and include the use of topical therapies, systemic antibiotics, hormonal therapies, and a wide range of immunomodulating medications. An evidence-based guideline is presented to support health care practitioners as they select optimal medical management strategies and is reviewed in this second part of the management guidelines. A therapeutic algorithm informed by the evidence available at the time of the review is provided.
Topics: Administration, Oral; Administration, Topical; Androgen Antagonists; Anti-Bacterial Agents; Canada; Evidence-Based Medicine; Female; Hidradenitis Suppurativa; Humans; Immunosuppressive Agents; Injections, Intralesional; Male; North America; Practice Guidelines as Topic; Prognosis; Publications; Risk Assessment; Treatment Outcome; United States
PubMed: 30872149
DOI: 10.1016/j.jaad.2019.02.068 -
Modern Pathology : An Official Journal... Jan 2018Nonsurgical treatments for prostate cancer include androgen-deprivation therapy (ADT), radiation therapy (RT), ablative therapies, chemotherapy, and newly emerging... (Review)
Review
Nonsurgical treatments for prostate cancer include androgen-deprivation therapy (ADT), radiation therapy (RT), ablative therapies, chemotherapy, and newly emerging immunotherapies. These approaches can be used alone or in combination depending on the clinical scenario. ADT is typically reserved for high-risk locally or systemically advanced disease that is not amenable to curative surgery. Radiation therapy can be used instead of surgery as primary therapy with curative intent for low-intermediate-risk disease as well as for control of locally advanced disease not suitable for surgery. Ablative therapies can be used as primary therapy for low-intermediate-risk disease or as salvage therapy for clinically localized disease where RT has failed. Chemotherapy and immune-based therapies are currently used for androgen-independent disease, although the indications for these approaches may well change as new data from clinical trials accrue. Pathologists should be able to recognize tissue changes associated with these treatments to provide information that will optimize patient management. This is particularly true in situations where clinical history of recent or remote nonsurgical treatment is not provided with the specimen. In the absence of this information, pathologists encountering the features described herein are encouraged to review patient records or communicate directly with clinical colleagues to determine how a given patient was treated and when.
Topics: Androgen Antagonists; Cryotherapy; Dietary Supplements; Drug Therapy; Extracorporeal Shockwave Therapy; Humans; Immunotherapy; Laser Therapy; Male; Neoplasm Grading; Photochemotherapy; Prostatic Neoplasms; Treatment Outcome
PubMed: 29297495
DOI: 10.1038/modpathol.2017.158 -
Science (New York, N.Y.) May 2009Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called...
Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
Topics: Androgen Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Biological Availability; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; DNA; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Tosyl Compounds; Transcription, Genetic; Xenograft Model Antitumor Assays
PubMed: 19359544
DOI: 10.1126/science.1168175 -
Oncology Research and Treatment 2020
Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins
PubMed: 32428911
DOI: 10.1159/000507053 -
Cancer Research Oct 2023Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression.
SIGNIFICANCE
Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.
Topics: Male; Humans; Receptors, Androgen; Androgen Antagonists; Androgens; Prostatic Neoplasms, Castration-Resistant; Ferroptosis; Nitriles; Castration; Cell Line, Tumor; Drug Resistance, Neoplasm
PubMed: 37527336
DOI: 10.1158/0008-5472.CAN-23-0285 -
Endocrinology Sep 2021In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through... (Review)
Review
In the treatment of metastatic prostate cancer, resistance to hormonal therapy is a major obstacle. With antiandrogen therapies that suppress androgen signaling through the androgen receptor (AR), the primary driver of prostate cancer, some malignancies are able take advantage of the closely related glucocorticoid receptor (GR). Escape from AR dependency often involves a simple functional switch from 1 steroid receptor to another. Recent research efforts have outlined the mechanism enabling this switch, which involves alterations in glucocorticoid metabolism that occur with antiandrogen therapy to increase tumor tissue glucocorticoids and enable GR signaling. Targeting this mechanism pharmacologically by blocking hexose-6-phosphate dehydrogenase shows promise in normalizing glucocorticoid metabolism and restoring responsiveness to antiandrogen therapy. This perspective reviews what we have learned about this resistance mechanism, examines potential implications, and considers how this knowledge might be harnessed for therapeutic benefit.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Glucocorticoids; Humans; Male; Metabolic Networks and Pathways; Molecular Targeted Therapy; Prostatic Neoplasms
PubMed: 34180973
DOI: 10.1210/endocr/bqab132 -
Revue Medicale de Liege Oct 2022Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of...
Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of treatment for advanced prostate cancer. In the metastatic setting, although ADT is initially effective, castration-resistant disease eventually develops in almost all men with prostate cancer. Since 2015, the addition of docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide with docetaxel to ADT has been shown to improve overall survival (OS) of patients starting ADT for metastatic disease. Castration resistance occurs when disease progresses despite testosterone in the castrate range most commonly with or, more rarely, without detectable metastases. The addition of next-generation antiandrogens to ADT has been shown to improve OS in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) identified by a PSA doubling time (DT) ? 10 months. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor without agonist activity. When added to ADT apalutamide has been shown to improve OS by 35 % in patients starting ADT for metastatic prostate cancer both in patients with upfront metastatic disease or after previous treatment with curative intent. Similarly apalutamide has been shown to provide a 14-month OS improvement in patients with nmCRPC and short PSA DT. These OS benefits were obtained at no cost in terms of quality of life. Apalutamide is given orally once a day and is well tolerated. The most common side effects are fatigue, rash, hypertension and hot flushes. Potential interactions with concomitant medication should be taken into account.
Topics: Androgen Antagonists; Androgens; Docetaxel; Gonadotropin-Releasing Hormone; Humans; Ligands; Male; Nonsteroidal Anti-Androgens; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Testosterone; Thiohydantoins
PubMed: 36226398
DOI: No ID Found