Cardiovascular morbidity in a randomized trial comparing GnRH-agonist and antagonist among patients with advanced prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5015-5015
Author(s):  
David Margel ◽  
Avivit Peer ◽  
Yaara Ber ◽  
Sivan Sela ◽  
Liat Shavit Grievink ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Absolute Risk ◽  
Absolute Risk Reduction ◽  
Cerebrovascular Event ◽  
Gnrh Agonists ◽  
Open Label ◽  
Gnrh Antagonists

5015 Background: Androgen-deprivation therapy (ADT) used in prostate-cancer may increase risk of cardiovascular disease (CVD). Limited preclinical and retrospective clinical data suggest that use of gonadotrophin-releasing hormone (GnRH)-antagonist may be associated with lower risk of CVD compared to GnRH-agonist. Methods: We conducted a randomized open-label study comparing the one year incidence of major cardiovascular and cerebrovascular event (MACCE) in prostate-cancer patients with pre-existing CVD commencing on GnRH-agonists or antagonists. Patients were followed every 3 months for the development of MACCE defined as either death, myocardial infarction (MI), cerebrovascular event (CVA), or percutaneous-coronary intervention (PCI). Serum levels of N-terminal pro-B-type natriuretic peptide (NTproBNP) were analyzed at baseline, 3, 6 and 12-months. Results: Eighty patients were enrolled (41 randomized to GnRH-antagonist, 39 to GnRH-agonist). Patients in both arms had similar age, baseline cardiovascular and prostate-cancer characteristics. During follow-up 15 patients developed a new cardiovascular event. Of these, nine patients developed MACCE (two deaths, one MI, two CVAs, and four PCI). Twenty percent (n = 8) of patients randomized to GnRH-agonists had a MACCE compared to 3% (n = 1) randomized to antagonists (log-rank p = 0.013). The absolute risk reduction for MACCE at 12 months using GnRH-antagonist was 18% (95%CI 5-31). Baseline levels of NTproBNP predicted events (AUC = 0.73 95%CI 0.54-0.91 p = 0.03) and increased over time only among patients with CV events. Conclusions: This is the first prospective study to test cardiovascular outcome among prostate-cancer patients receiving ADT. We demonstrated that in patients with pre-existing CVD, GnRH-antagonists was associated with development of fewer cardiovascular events compared to GnRH-agonists. Clinical trial information: NCT02475057.

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.

Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 200-200 ◽  
Author(s):  
Fred Saad ◽  
James L. Bailen ◽  
Christopher Michael Pieczonka ◽  
Daniel R. Saltzstein ◽  
Paul R. Sieber ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gnrh Antagonist ◽  
Phase 1 ◽  
Specific Antigen ◽  
Phase 2 ◽  
Open Label ◽  
Gnrh Antagonists ◽  
Parallel Group ◽  
Hot Flush ◽  
Secondary Endpoints

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T > 150 ng/dL and prostate-specific antigen (PSA) > 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T < 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T < 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over > 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( < 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.

scholarly journals Assessment and Mitigation of Cardiovascular Risk for Prostate Cancer Patients: A review of the evidence

2021 ◽  
Author(s):  
Patrick Davey ◽  
Kyriacos Alexandrou
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Risk Mitigation ◽  
Current Evidence ◽  
Gnrh Agonists ◽  
Gnrh Antagonists ◽  
Co Morbidity

Abstract Background: Cardiovascular disease (CVD) is a common co-morbidity in patients with prostate cancer. In this review, we summarise the published literature on the association of cardiovascular risk with androgen deprivation therapy (ADT) treatment and explore the potential differences between the gonadotropin-releasing hormone (GnRH) agonists and antagonists and the molecular mechanisms that may be involved. We also provide a practical outlook on the identification of underlying CV risk and explore the different stratification tools available. Results: While not definitive, the current evidence suggests that GnRH antagonists may be associated with lower rates of certain CV events vs agonists, particularly in patients with pre-existing CVD. We have reached this conclusion as the highest-grade evidence from randomised clinical trials comparing GnRH agonists verses antagonists is uniform in finding lower CV event rates with GnRH antagonists. Risk reduction strategies such as lifestyle advice, consideration of ADT modality, and co-medications may help to reduce CV risk factors and improve outcomes in prostate cancer patients receiving ADT. Conclusions: Given all the data that is currently available, identification of baseline CV risk factors may be key to risk mitigation in patients with prostate cancer receiving ADT.

scholarly journals Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial

Circulation ◽  
2021 ◽  
Author(s):  
Renato D. Lopes ◽  
Celestia S. Higano ◽  
Susan F. Slovin ◽  
Adam J. Nelson ◽  
Robert Bigelow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Gnrh Agonist ◽  
Primary Outcome ◽  
Gnrh Antagonist ◽  
Locally Advanced ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiovascular Safety ◽  
Gnrh Antagonists ◽  
Clinical Trial Registration

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908

The cardiovascular effects of gonadotropin-releasing hormone antagonists in men with prostate cancer

2021 ◽  
Author(s):  
Filipe Cirne ◽  
Nazanin Aghel ◽  
Jo-Anne Petropoulos ◽  
Laurence Klotz ◽  
Daniel J Lenihan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cardiovascular Events ◽  
Gnrh Antagonist ◽  
Cardiovascular Effects ◽  
Cardiovascular Death ◽  
Gonadotropin Releasing Hormone ◽  
Gnrh Agonists ◽  
Gnrh Antagonists ◽  
Releasing Hormone ◽  
Gonadotropin Releasing Hormone Antagonists

Abstract Aims The aim of this study was to determine whether gonadotropin-releasing hormone (GnRH) antagonists (an emerging class of drugs to suppress testosterone synthesis in the treatment of prostate cancer) cause less adverse cardiovascular events than the more commonly use GnRH agonists. Methods and results We conducted a systematic review to identify all randomized, controlled trials in which a GnRH antagonist was compared with a GnRH agonist in men with prostate cancer. We identified 10 eligible studies including two different GnRH antagonists, degarelix (n = 1681) and relugolix (n = 734), which were compared with the GnRH agonists, leuprolide (n = 714) and goserelin (n = 600). The pooled risk ratios (95% confidence intervals) among GnRH antagonist recipients for adverse cardiovascular events, cardiovascular death, and all-cause mortality were 0.57 (0.39–0.81); 0.49 (0.25–0.96); and 0.48 (0.28–0.83), respectively. Important limitations of the included trials were their short duration of follow-up, unblinded study design and (in most of the studies) the identification of adverse cardiovascular events through safety reporting mechanisms rather than as a pre-specified outcome. There was no evidence of heterogeneity of findings among the studies. Conclusions There is consistent but methodologically limited data to suggest that GnRH antagonists—a relatively new class of androgen deprivation therapy for prostate cancer—cause significantly less cardiovascular adverse effects than the more frequently used GnRH agonists.

A switch from GnRH agonist to GnRH antagonist in castration-resistant prostate cancer patients leads to a low response rate on PSA

2012 ◽  
Vol 31 (2) ◽  
pp. 339-343 ◽  
Author(s):  
Alexandra Masson-Lecomte ◽  
Laurent Guy ◽  
Philippe Pedron ◽  
Franck Bruyere ◽  
Morgan Rouprêt ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Response Rate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Efficacy of treatment with a GnRH antagonist in prostate cancer patients previously treated with a GnRH agonist

2015 ◽  
Vol 76 (2) ◽  
pp. 301-306
Author(s):  
Taisuke Ezaki ◽  
Takeo Kosaka ◽  
Ryuichi Mizuno ◽  
Toshiaki Shinojima ◽  
Eiji Kikuchi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Previously Treated ◽  
Efficacy Of Treatment

scholarly journals Cardiovascular risk profiles of GnRH agonists and antagonists: real-world analysis from UK general practice

2020 ◽  
Author(s):  
Patrick Davey ◽  
Mike G. Kirby
Keyword(s):  
Prostate Cancer ◽  
Primary Care ◽  
Gnrh Agonist ◽  
Real World ◽  
Cardiac Event ◽  
Gnrh Antagonist ◽  
Gnrh Agonists ◽  
Cardiac Events ◽  
Real World Data ◽  
The Uk

Abstract Purpose Androgen deprivation therapy (ADT) is the mainstay for the management of metastatic prostate cancer. Available pharmaceutical ADTs include gonadotropin-releasing hormone (GnRH) agonists and antagonists. Here, real-world data are presented from the UK general practitioner Optimum Patient Care Research Database. The study investigated the hypothesis that GnRH antagonists have lower cardiac event rates than GnRH agonists. Methods The incidence of cardiac events following initiation of GnRH antagonist or agonist therapy was investigated in a population-based cohort study conducted in UK primary care between 2010 and 2017. Results Analysis of real-world data from the UK primary care setting showed that relative risk of experiencing cardiac events was significantly lower with degarelix, a GnRH antagonist, compared with GnRH agonists (risk ratio: 0.39 [95% confidence interval 0.191, 0.799]; p = 0.01). Patients that received degarelix as first-line treatment switched treatment more frequently (33.7%), often to a GnRH agonist, than those who initiated treatment with a GnRH agonist (6.7–18.6%). Conclusion Screening for known or underlying vascular disease and identifying those at high risk of a cardiac event is important for risk mitigation in patients with prostate cancer receiving hormone therapy. The GnRH antagonist degarelix conferred a significantly lower risk of cardiac events than GnRH agonists. Prior to treatment, patients should be stratified based on level of cardiovascular (CV) risk, and appropriate lifestyle, and pharmacological interventions to mitigate CV risk should be recommended. CV risk factors and patient response to the intervention should be monitored at regular intervals.

scholarly journals A Case of Switching from GnRH Agonist to Antagonist for Castration Resistant Prostate Cancer Control

2019 ◽  
Vol 12 (3) ◽  
pp. 688-692 ◽  
Author(s):  
Rumiko Sugimura ◽  
Takashi Kawahara ◽  
Yasuhide Miyoshi ◽  
Masahiro Yao ◽  
Sawako Chiba ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gnrh Agonist ◽  
Gnrh Antagonist ◽  
Cancer Control ◽  
Castration Resistant Prostate Cancer ◽  
Gnrh Antagonists ◽  
Leuprorelin Acetate ◽  
Prostate Needle Biopsy ◽  
2Nd Generation ◽  
Castration Resistant

GnRH antagonist and GnRH agonist are widely used as androgen deprivation therapy for metastatic prostate cancer. A previous report demonstrated that patients with PSA levels of >20 ng/mL using GnRH antagonists showed favorable outcomes in comparison to those using GnRH agonists. An 82-year old male patient with edema, a stony hard nodule on his prostate, and an initial PSA level of 6,717 ng/mL was referred to our hospital due to suspected prostate cancer. He received prostate needle biopsy and was diagnosed with prostate cancer with bone metastasis, with a Gleason Score of 4 + 4 = 8. He was then treated with a GnRH agonist (leuprorelin acetate) and bicalutamide from July 2015. Although his PSA level decreased to 582.0 ng/mL in December 2015, his PSA level gradually increased and CRPC developed. He indicated that he did not wish to take 2nd generation anti-androgen drugs or receive systemic chemotherapy. We introduced a GnRH antagonist (degarelix) in February 2015; his PSA level did not change and his CRPC was controlled. We herein report a case in which changing a GnRH agonist to a GnRH antagonist contributed to CRPC control.

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