Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease

2019 ◽  
Vol 202 (6) ◽  
pp. 1199-1208 ◽  
Author(s):  
David Margel ◽  
Avivit Peer ◽  
Yaara Ber ◽  
Liat Shavit-Grievink ◽  
Tzlil Tabachnik ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cardiovascular Disease ◽  
Randomized Trial ◽  
Gnrh Agonist ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Cardiovascular Morbidity

scholarly journals Experience with degarelix in the treatment of prostate cancer

2012 ◽  
Vol 5 (1) ◽  
pp. 11-24 ◽  
Author(s):  
Neal D. Shore
Keyword(s):  
Prostate Cancer ◽  
Gnrh Agonist ◽  
Clinical Studies ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Serum Alkaline Phosphatase ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Similar Efficacy ◽  
First Line

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.

Abstract 17016: Cardiovascular Safety Profile of Gonadotropin Releasing Hormone (GnRH) Antagonist Compared to GnRH Agonist Among Patients With Prostate Cancer: A Meta-Analysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Courtney Campbell ◽  
Daniel Addison ◽  
Ragavendra Baliga ◽  
Ajay Vallakati
Keyword(s):  
Prostate Cancer ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Gnrh Agonist ◽  
Cardiovascular Events ◽  
Gnrh Antagonist ◽  
Gnrh Agonists ◽  
Cardiovascular Safety ◽  
Gnrh Antagonists ◽  
Artery Disease

Introduction: Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer therapy. The degree that ADT contributes to cardiovascular disease remains uncertain with conflicting studies. ADT can be achieved through the use of gonadotrophin releasing (GnRH) hormone agonist or, more recently, GnRH antagonists. The objective of this study was to determine whether cardiovascular events differ after the initiation of GnRH agonist compared with GnRH antagonist in randomized control trials. Methods: From PubMed, Cochrane Central, and Embase we identified all randomized studies comparing GnRH antagonists with GnRH agonists in patients with prostate cancer from 2000-2020. Outcomes studied included major adverse cardiovascular events (MACE), coronary artery disease (CAD), cerebrovascular accidents (CVA), atrial fibrillation (AF), and heart failure (HF). A random effects model using the Mantel-Haenszel method was used to assess outcomes. Results: Overall, we identified 7 studies (n = 3298) which reported outcomes in prostate cancer patients receiving GnRH antagonists (n = 2127) compared with those receiving GnRH agonists (n = 1171). When compared to men receiving GnRH agonists, the incidence of MACE (RR 0.52, 95% CI 0.35-0.76, p<0.001) and CAD (RR 0.46, 95% CI 0.27 - 0.77, p=0.004) was lower in men receiving GnRH antagonists. There was no difference in the rates of CVA (RR 0.93, 95% CI 0.31-2.77, p=0.89), AF (RR 0.49, 95% CI 0.09-2.72, p=0.41), or HF (RR 0.55, 95% CI 0.19-1.59, p=0.52) between the two groups. Conclusion: For men with prostate cancer receiving ADT, GnRH antagonists decreased the incidence of MACE and coronary artery disease by half compared to men treated with GnRH agonists. GnRH antagonists have a more favorable cardiovascular safety profile than GnRH agonists.

scholarly journals Switching from a GnRH agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis

2019 ◽  
Vol 14 (2) ◽  
Author(s):  
Kaleem S. Atchia ◽  
Christopher J.D. Wallis ◽  
Neil Fleshner ◽  
Paul Toren
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Meta Analysis ◽  
Specific Antigen ◽  
Patient Characteristics ◽  
Agonist Therapy ◽  
Clinical Responses ◽  
Key Terms

Introduction: We sought to address whether there are clinical responses when patients who are failing gonadotropin-releasing hormone (GnRH) agonist therapy are switched to degarelix. Androgen-deprivation therapy remains the backbone of treatment for disseminated prostate cancer and may be achieved with orchiectomy, GnRH agonists, or degarelix, a GnRH antagonist. Methods: To perform a systematic review and meta-analysis, a search of the BIOSIS Previews, Embase, International Pharmaceutical Abstracts, MEDLINE, and Google Scholar databases was performed using key terms. Quantitative meta-analysis was performed to provide a pooled estimate of prostate-specific antigen (PSA) response at three months. Results: Thirteen studies were identified, eight of which were included in the qualitative and quantitative analyses. Patient characteristics were broadly similar between the studies. Out of 155 patients across all included studies, 20 had stable PSA after the switch (12.9%), 14 had between 10‒30% decrease in PSA (9.0%), three had between 30‒50% decrease (1.9%), and 13 had more than 50% decrease (8.4%). Random effects meta-analysis of these data demonstrated a pooled response rate of 27.75 (95% confidence interval 18.9‒36.5%; I2=7.9%). Changes in testosterone levels following the switch could not be quantitatively assessed due to lack of sufficient data. Conclusions: Our results suggest that a switch to GnRH antagonist following progression on a GnRH agonist may result in a stable or decreased PSA at three months in about 30% of patients. This information should be considered among the potential options to discuss with patients with a rising PSA on GnRH agonist therapy.

Determination of the ability of a novel, long-acting subcutaneous GnRH antagonist, VERU-100, to castrate without a testosterone surge in a rat model.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 128-128
Author(s):  
Robert H. Getzenberg ◽  
Jui-Chen Lin ◽  
Andrew Cerro ◽  
Christopher A. Rhodes ◽  
Mitchell S. Steiner
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Gnrh Antagonist ◽  
Animal Health ◽  
High Volume ◽  
Dose Finding ◽  
Loading Dose ◽  
Sprague Dawley ◽  
Gnrh Antagonists ◽  
Diagnostic Center

128 Background: Androgen deprivation therapy (ADT) is the mainstay for the treatment of advanced prostate cancer. LHRH agonists are frequently used for ADT but these agents often result in initial surges in testosterone (T) levels. Although they do not result in initial T surges, current injectable GnRH antagonists are short term (1 month) subcutaneous (sc) depots that require a high volume loading dose followed by monthly maintenance dosing. VERU-100 is a novel GnRH decapeptide antagonist for long term suppression of T to castrate levels and is administered as a low volume sc injection without the requirement of a loading dose. Eight distinct formulations were evaluated in rats in order to select the best formulation, VERU-100. Methods: Male Sprague Dawley rats (n=3 per group) were injected sc through a 21G needle, with approximately 200 μl of each formulation at a dose level of 20 mg/kg. Eight groups consisting of the distinct test formulations were evaluated. Blood samples were drawn at weekly intervals until week 4 and then bi-weekly for pharmacokinetic (PK) (Integrated Analytical Solutions) and testosterone (T) level determinations (Cornell University Animal Health Diagnostic Center). Results: Within approximately 24 hours after administration of the GHRH antagonist formulations, testosterone levels in the rats went from a mean of 7.36 ng/ml to undetectable. The T levels resulting from a single injection of the lead formulation in these studies, VH-030-002, remained undetectable for greater than 26 weeks (6 months) as did the other formulations tested. The corresponding PK analysis demonstrated that the GnRH antagonist levels were detectable for greater than 26 weeks and remained above 1 ng/ml for almost all of the study points. The T levels correlated to the exposure from the formulations, and PKPD was as consistent for GnRH antagonists. Conclusions: VERU-100 is a novel GnRH antagonist formulation that in this rodent study, with a low injection volume, resulted in undetectable T for at least six months. No surge of T is observed after administration. An IND submission is anticipated in early 2020 for the dose finding Phase 2 trial in men with advanced prostate cancer.

scholarly journals Impact of the Duration of Adjuvant Hormonal Therapy in Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy: A Secondary Analysis of RTOG 85-31

2009 ◽  
Vol 27 (13) ◽  
pp. 2137-2143 ◽  
Author(s):  
Luis Souhami ◽  
Kyounghwa Bae ◽  
Miljenko Pilepich ◽  
Howard Sandler
Keyword(s):  
Prostate Cancer ◽  
Regression Model ◽  
Randomized Trial ◽  
Hormonal Therapy ◽  
Advanced Prostate Cancer ◽  
Locally Advanced ◽  
Radiation Therapy Oncology Group ◽  
Disease Free Survival ◽  
Adjuvant Hormonal Therapy ◽  
Locally Advanced Prostate Cancer

PurposeRadiation Therapy Oncology Group 85-31 was a randomized trial of androgen suppression for life for patients with locally advanced prostate cancer. However, not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrence. We correlated duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued hormonal therapy.Patients and MethodsThe protocol mandated pelvic radiotherapy followed by goserelin given indefinitely or until disease progression. There were 189 analyzable patients. Patients were divided in groups based on the tertile of hormonal therapy duration (HTD) as follows: ≤ 1 year, more than 1 year and ≤ 5 years, and more than 5 years. Overall survival (OS), disease-free survival (DFS), cause-specific mortality, local failure (LF), and distant metastasis (DM) were studied. Kaplan-Meier estimation and Cox proportional hazards regression model were used for OS and DFS, and Fine and Gray's regression model was used for the other outcomes.ResultsThe median follow-up for surviving patients is 9.6 years. The median duration of adjuvant hormonal therapy was 2.2 years. The HTD more than 5 years group is significantly associated with an improved survival and DFS and fewer DMs than other HTD groups. After adjustment for age, radical prostatectomy, nodal status, Gleason score, and stage variables, the HTD more than 5 years group remains significantly associated with better OS and DFS than other HTD groups.ConclusionIn this hypothesis-generating analysis, prolonged HTD of more than 5 years seems significantly associated with improvements in most outcomes. Given these data, decreasing HTD to ≤ 5 years may have a detrimental effect on patients with locally advanced prostate cancer. Only a randomized trial will conclusively clarify this issue.

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