Degarelix for treating advanced hormone-sensitive prostate cancer.
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ABSTRACT:
SUBMITTER: Zengerling F
PROVIDER: S-EPMC8407409 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Degarelix for treating advanced hormone-sensitive prostate cancer.
Zengerling Friedemann F Jakob Joachim J JJ Schmidt Stefanie S Meerpohl Joerg J JJ Blümle Anette A Schmucker Christine C Mayer Benjamin B Kunath Frank F
The Cochrane database of systematic reviews 20210805
<h4>Background</h4>Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy.<h4>Objectives</h4>To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer.<h4>Search methods</h4>We searched multiple databases (CENTRAL, MEDLINE, Embase, ...[more]
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Project description:BackgroundTo explore the effectiveness and safety of the gonadotropin-releasing hormone antagonist, Degarelix, for the treatment of advanced hormone-dependent prostate cancer (PCa) in a real-world setting.MethodsIn this noninterventional study, patients with advanced hormone-dependent PCa were included. Primary endpoints were progression-free survival (PFS) failure defined as either prostate-specific antigen failure, additional therapy related to PCa, or death. Secondary endpoints included patient and physician satisfaction scores, urinary symptoms, and adverse events (AEs).ResultsOf 274 patients with PCa, 271 received at least 1 dose of Degarelix. At a median follow-up of 12.2 (interquartile range 6.2-22.0) months, 148 patients (60.2%) had PFS failure. Thirty-five patients (13%) withdrew from the study due to AEs, 23 patients (8.4%) died, and 36 patients (13%) completed 3 years' follow-up. Urinary symptoms significantly decreased over time. In the safety population, 87.8% of patients reported AEs, with injection-site reactions commonly reported. The majority of physicians and patients considered the therapy satisfactory and well tolerated.ConclusionsIn this observational study, Degarelix treatment was well accepted by men with advanced hormone-dependent PCa. Compared with phase III studies, a higher proportion of patients had PFS failure, possibly due to the inclusion of men with more advanced disease in the current study, and more men reported AEs.
| S-EPMC8772641 | biostudies-literature
Project description:ObjectivesThis study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist.BackgroundTreatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist.MethodsPRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses.ResultsAs of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease.ConclusionsPRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908).
| S-EPMC8352040 | biostudies-literature
Project description:Our aim was to systematically evaluate the benefits of degarelix as antagonist versus agonists of gonadotropin-releasing hormones (GnRH) for the treatment of advanced prostate cancer (PC). This comparison was performed either in terms of biochemical or oncological or safety profiles. To this end we, carried out a systematic review and meta-analysis of the literature.We selected only studies directly and prospectively analyzing the two treatments in the same population (randomized phase III studies). We followed the Preferred Reporting Items for Systematic Reviews and meta-analyses process for reporting studies.After we eliminated studies according to the exclusion criteria, 9 publications were considered relevant to this review. These articles described 5 clinical trials that were eligible for inclusion. The follow-up duration in all trials did not exceed 364 days. This meta-analysis and review comprised a total of 1719 men, 1061 randomized to degarelix versus 658 to GnRH agonists treatment for advanced PC. Oncological results were evaluated only in 1 trial (CS21:408 cases) and they were not the primary endpoints of the study. Treatment emerging adverse events were reported in 61.4% and 58.8% of patients in the degarelix and GnRH agonists group, respectively (odds ratio, OR = 1.17; 95% confidence interval, 95% CI: 0.78-1.77, P?>?0.1). Treatment related severe cardiovascular side effects were reported (trial CS21-30-35) in 1.6% and 3.6% of patients in the degarelix and GnRH agonists group, respectively (OR = 0.55, 95% CI: 0.26-1.14, P?>?0.1).Our analysis evidences relevant limitations in particular for the comparative evaluation of the efficacy and the oncological results related to degarelix.
| S-EPMC5058791 | biostudies-other
Project description:Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer-related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa.
| S-EPMC3474961 | biostudies-literature
Project description:BackgroundAndrogen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone.MethodsWe assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone.ResultsA total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%.ConclusionsSix cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.).
| S-EPMC4562797 | biostudies-literature
Project description:As the overall population ages, the proportion of elderly patients (aged ≥65 years) with breast cancer also increases. Studies have shown that elderly patients with hormone receptor-positive breast cancer can derive as much benefit from treatment as do younger patients, yet they remain underrepresented in clinical trials and are often undertreated in clinical practice. Treatment decisions for older patients should not be based solely on chronologic age; a patient's physiologic functioning and comorbidities must also be taken into consideration. For recurrent or metastatic disease, systemic treatment with endocrine therapies or chemotherapy may prolong a patient's life and alleviate troublesome symptoms. Resistance to therapy remains a problem in the advanced breast cancer setting, with most patients eventually becoming resistant to additional treatment. New combination regimens that target multiple pathways, such as everolimus plus exemestane, have shown efficacy in elderly patients previously resistant to endocrine therapies, and future research may need to focus on such combinations in order to improve outcomes in this patient group. A number of investigational agents are in clinical development, although few studies identify their effects in the elderly patient population. Optimizing effective yet tolerable therapeutic regimens for elderly patients could improve their outcomes while ensuring that the goals of improved survival and quality of life are considered.
| S-EPMC4550185 | biostudies-literature
Project description:Degarelix is a gonadotrophin-releasing hormone (GnRH) antagonist for the first-line treatment of androgen-dependent advanced prostate cancer. It has a direct mechanism of action that blocks the action of GnRH on the pituitary with no initial surge in gonadotrophin or testosterone levels. Degarelix is the most extensively studied and widely available GnRH antagonist worldwide. Clinical studies have demonstrated similar efficacy to the GnRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. However, degarelix produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surge or microsurges, thus preventing the risk of clinical flare in advanced disease. Clinical trials have demonstrated that degarelix can offer improved disease control when compared with a GnRH agonist in terms of superior PSA progression-free survival (suggesting that degarelix likely delays progression to castration-resistant disease), and a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is generally well tolerated, with no reports of systemic allergic reactions in any clinical studies. In conclusion, degarelix offers clinicians a rational first-line hormonal monotherapy option for the management of advanced prostate cancer.
| S-EPMC3547532 | biostudies-literature
Project description:BackgroundDarolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.MethodsIn this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.ResultsThe primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).ConclusionsIn this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).
| S-EPMC9844551 | biostudies-literature
Project description:Loss of the histone demethylase KDM5D (lysine-specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP-seq) of the LNCaP cell line (androgen-sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2-binding sites were analyzed. Associations between MYBL2 mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone-sensitive prostate cancer. In vitro assays with silencing and overexpression of MYBL2 and KDM5D in androgen receptor (AR)-positive hormone-sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing KDM5D increased histone H3 lysine K4 (H3K4) trimethylation and increased MYBL2 expression. KDM5D and MYBL2 were negatively correlated with some but not all clinical samples. Higher MYBL2 expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower MYBL2 levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes. In vitro, modifications of KDM5D and MYBL2 altered cell cycle distribution and apoptosis in a cell line-specific manner. These results show that the transcription factor MYBL2 impacts in vitro hormone-sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone-sensitive prostate cancer.
| S-EPMC9718114 | biostudies-literature
Project description:Darolutamide (NUBEQA®) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).
| S-EPMC10517889 | biostudies-literature