Factors contributing to non‐adherence to
            GnRH
            agonists in men with prostate cancer

Purpose Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. Methods By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. Results From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. Conclusion Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.

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

Circulation ◽

10.1161/circ.142.suppl_3.17016 ◽

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.

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Lower odds of cardiac events for gonadotropic releasing hormone antagonists versus agonists.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.34 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 34-34 ◽

Cited By ~ 1

Author(s):

Eugene Blanchard Cone ◽

Maya Marchese ◽

Stephen Reese ◽

Junaid Nabi ◽

Kerry L. Kilbridge ◽

...

Keyword(s):

Prostate Cancer ◽

Myocardial Infarction ◽

Cardiac Toxicity ◽

World Health ◽

Reporting Odds Ratio ◽

Gnrh Agonists ◽

Cardiac Events ◽

First Line ◽

Gnrh Antagonists ◽

Releasing Hormone

34 Background: Gonadotropic releasing hormone (GnRH) agonists and antagonists are first-line for advanced prostate cancer, but may be associated with cardiac toxicity. Observational studies show a relatively lower risk for GnRH antagonists, but a randomized trial found no difference. We compared the reporting of cardiac events for GnRH agonists and antagonists. Methods: We used VigiBase, the World Health Organization global database of case safety reports, which collects data from more than 130 countries to extract drug-adverse event (AE) pairs. Using Medical Dictionary for Regulatory Activities terminology, we identified AEs related to GnRH antagonist (degarelix) or agonist (leuprolide, goserelin, triptorelin, histrelin) therapy for prostate cancer, including myocardial infarction, heart failure, cardiomyopathies, new-onset valvular dysfunction, and other major cardiac events. To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected. Results: We found 10,504 AEs for GnRH agonists, and 1,606 for GnRH antagonists; 805 (7.7%) were cardiac for agonists, and 102 for antagonists (6.4%). We found no signal for overall cardiac events or any subgrouping for GnRH antagonists, but identified a signal both for overall cardiac events (ROR 1.20, 95% CI 1.12-1.29) and myocardial infarction (1.76, 1.57-1.97) for GnRH agonists. Conclusions: Using validated pharmacovigilance methodology, we found a signal for myocardial infarction for GnRH agonists, but did not detect one for GnRH antagonists. As cardiovascular disease is the most common cause of non-cancer death in prostate cancer patients, this finding is of specific relevance in the current era of novel second-line anti-androgen therapies which may compound toxicity when added to first-line therapy. The relative cardiac toxicity of GnRH agonist therapy compared to GnRH antagonists merits renewed attention.

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GnRH agonists and antagonists decrease the metastatic progression of human prostate cancer cell lines by inhibiting the plasminogen activator system

Oncology Reports ◽

10.3892/or.15.2.393 ◽

2006 ◽

Cited By ~ 4

Author(s):

D. Dondi ◽

C. Festuccia ◽

M. Piccolella ◽

M. Bologna ◽

M. Motta

Keyword(s):

Prostate Cancer ◽

Plasminogen Activator ◽

Prostate Cancer Cell ◽

Gnrh Agonists ◽

Metastatic Progression ◽

Human Prostate Cancer ◽

Human Prostate Cancer Cell ◽

Prostate Cancer Cell Lines ◽

Plasminogen Activator System ◽

Activator System

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

10.21203/rs.3.rs-382729/v1 ◽

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.

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Influence of androgen deprivation therapy on glucose metabolism and ambulatory glucose profile

Medical Council ◽

10.21518/2079-701x-2021-7-172-182 ◽

2021 ◽

pp. 172-182

Author(s):

E. Yu. Grickevich ◽

D. V. Skuridina ◽

S. N. Perekhodov

Keyword(s):

Prostate Cancer ◽

Glucose Metabolism ◽

Androgen Deprivation Therapy ◽

Locally Advanced ◽

Androgen Deprivation ◽

Glucose Metabolism Disorders ◽

Gnrh Agonists ◽

Glucose Profile ◽

Freestyle Libre

Introduction. Androgen deprivation, used to treat prostate cancer, leads to metabolic disorders, including glucose metabolism disorders. The timing of development and the characteristics of these changes have not been sufficiently studied. The expansion of the possibilities for assessing glycemia makes it possible to obtain changes in glucose.Objective. To study the dynamics of the effect of long-term androgen-deprivation therapy with gonadotropin-releasing hormone agonists (GnRH agonists) on the parameters of glucose metabolism and ambulatory glucose profile in patients with locally advanced prostate cancer (La PCa).Materials and methods. The study included 99 patients with La PCa receiving androgendeprivation therapy (ADT) with (GnRH agonists) for at least 12 months. The study of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels was performed at baseline, after 3, 6 and 12 months of ADT, and constant self-monitoring of glycemia was recommended using portable glucometers. Flash glucose monitoring systems (FreeStyle Libre) were installed in ten patients with a detected increase in glycemia on the background of ADT, allowing them to obtain data on the ambulatory glucose profile (AGP).Results and discussion. Long-term ADT in patients with La PCa, regardless of baseline age, BMI, WC, was accompanied by an early, progressive deterioration in parameters of glucose metabolism. The proportion of patients with prediabetic FPG values after 12 months becames 66% according ADA criteria. We found that 12-month ADT changes the AGP: an increase area under the curve and postprandial glycemic levels, an increase in blood glucose variability with an increase in the CONGA index to 6.817 (p < 0.001).Conclusion. ADT by GnRH agonists in patients with La PCa is accompanied by a predisposition to early disorders of glucose metabolism with a high risk of rapid development of prediabetes regardless of baseline age, BMI, and WC. The AGP of patients is characterized by an increase in the total glycemic load, and glycemic variability.

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Exploring the Association Between Prostate Cancer Diagnosis per se and use of GnRH Agonists and Diabetes Control in Men with type 2 Diabetes Mellitus: A Nationwide, Population-Based Cohort Study

10.21203/rs.3.rs-599963/v1 ◽

2021 ◽

Author(s):

E Lin ◽

Hans Garmo ◽

Mieke Hemelrijck ◽

Jan Adolfsson ◽

Pär Stattin ◽

...

Keyword(s):

Prostate Cancer ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cohort Study ◽

Population Based ◽

Diabetes Control ◽

Gnrh Agonists ◽

Cancer Data

Abstract Background: Gonadotropin Releasing Hormones agonists (GnRH), which are first line treatment for metastatic prostate cancer (PCa), increase risk of type 2 diabetes mellitus (T2DM). This study aims to quantify the association of use of GnRH with diabetes control in PCa men with T2DM.Methods: Nationwide population-based cohort study in the Swedish National Diabetes Register and Prostate Cancer data Base Sweden 4.1, on the association between GnRH and diabetes control in T2DM men with PCa by comparing T2DM men with PCa vs. without PCa, as well as comparing T2DM men with PCa on or not on GnRH. The primary exposure was use of GnRH. Worsening diabetes control was the primary outcome, defined as: 1) increase of HbA1c to 58 mmol/mol or higher; 2) HbA1c increase by 10 mmol/mol or more; 3) Start of antidiabetic drugs or switch to insulin; 4) combine all definitions above. Cox proportional hazards regression was used to analyze the association. Results: There were 5,714 T2DM men with PCa of whom 692 were on GnRH and 28,445 PCa-free men with T2DM with similar baseline characteristics. Diabetes control was worse in men with GnRH vs. PCa-free men (HR: 1.24, 95% CI: 1.13-1.34) as well as compared with PCa men without GnRH (HR:1.58, 95% CI: 1.39-1.80). Conclusion: Use of GnRH in T2DM men with PCa was associated with worse glycemic control. The findings highlight the need to closely monitor diabetes control in men with T2DM and PCa starting GnRH agonists and to limit the duration of their use when possible.

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The Association between the Risk of Cardiovascular Disease and Androgen Deprivation Therapy in Patients with Prostate Cancer. A Meta-Analysis and systematic review.

10.21203/rs.2.10884/v3 ◽

2019 ◽

Author(s):

Zhen Liang ◽

Jun Zhu ◽

Xiaoxin Duo ◽

Shangheng Shi ◽

Yawei Xu ◽

...

Keyword(s):

Prostate Cancer ◽

Heart Failure ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Meta Analysis ◽

Androgen Deprivation ◽

Relative Risk Ratio ◽

Control Group ◽

Gnrh Agonists ◽

Increased Risk

Abstract Background : Androgen deprivation therapy (ADT) is widely being applied in men who suffered from prostate cancer, our aim is to evaluate whether ADT is associated with an excess risk of cardiovascular disease (CVD). Method : Studies comparing the the incidence of CVD between ADT group and control group were identified through literature search in electronic databases (Pubmed, Embase, Web of Science) until July 2019 and only observational studies and randomized controlled trials (RCT) were included. The estimating relative risk ratio (RR) and 95% confidence intervals (CI) were calculated through random effects meta-analyses. Result : A statistically significant association was detected for acute myocardial infarction (AMI) with RR = 1.22; 95% confidence interval CI, 1.05–1.43; P< 0.05. Significant relationship between coronary heart disease (CHD) and ADT was also observed, with summary RR=1.19; 95%CI, 1.03-1.38; P<0.05. ADT was associated with a risk increasement for heart failure (HF) with RR=1.15; 95% CI 1.01–1.33; P< 0.05. On the contrary, ADT was not associated with an increased risk of sudden cardiac death (SCD). Conclusions : From this study, ADT is associated with increased risk of AMI, CHD, and heart failure (HF); in contrast, this association is not detected in SCD; various modalities of ADT could significantly increase the risk of CHD, AMI, except for oral anti-androgen (AA). Our meta-analysis also suggests that the long-term application of ADT in prostate cancer patients would not result in a significant increase in AMI incidence compared with short-term. Moreover, the combined application of AA and GnRH agonists would lead to a similar risk of AMI compared with orchiectomy or GnRH agonists monotherapy whereas higher risk of CHD was detected when compared GnRH agonists plus AA with orchiectomy.

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REPRODUCTIVE FUNCTION AND ANTITUMOR ACTIVITY: DIFFERENT ROLES FOR THE HYPOTHALAMIC HORMONE GnRH

Istituto Lombardo - Accademia di Scienze e Lettere - Incontri di Studio ◽

10.4081/incontri.2019.610 ◽

2020 ◽

Author(s):

Patrizia Limonta ◽

Marcella Motta ◽

Roberta M. Moretti ◽

Monica Marzagalli ◽

Fabrizio Fontana ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Biological Effects ◽

Molecular Target ◽

Cytotoxic Drug ◽

Gnrh Agonists ◽

Gnrh Analog ◽

Androgen Ablation ◽

Hypothalamic Hormone ◽

Wide Range

The decapeptide GnRH (Gonadotropin-Releasing Hormone), whose amino acidic sequence was discovered by Dr. A.V. Schally, was initially identified as the key hypothalamic hormone involved in the control of reproductive functions. GnRH, by binding to specific receptors (GnRH-R) at the pituitary level, stimulates the synthesis and secretion of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormone) and the downstream production of steroid hormones at the gonadal level. At present, these receptors represent the molecular targets of the standard pharmacological treatments for hormone-related tumors, such as androgen-dependent prostate cancer. Actually, chronic administration of synthetic GnRH agonists induces the desensitization of pituitary receptors and, subsequently, the suppression of testicular androgen production. The physiological role of GnRH in reproductive functions, and its regulation, represented a very important line of research for professor Martini and His colleagues. In the last three decades it has become increasingly clear that GnRH-R are expressed also in a wide range of tumors, both related and unrelated to the reproductive system; in particular GnRH-R are expressed in prostate cancers after development of resistance to androgen ablation therapy (castration resistant prostate cancer, CRPC), a tumor known to be refractory to standard chemotherapy. Activation of these receptors by means of GnRH agonists is associated with a significant antiproliferative/antimetastatic/antiangiogenic activity. These different biological effects at pituitary vs. prostate tissues are related to specific intracellular signal transduction pathways. Based on these observations, tumor GnRH-R are presently considered an effective molecular target for novel therapies (‘targeted’ therapies). In particular, GnRH-based bioconjugates, in which a standard cytotoxic drug is linked to a GnRH analog, have been developed. The rationale for this ‘targeted’ therapy is that the GnRH analog behaves as the targeting moiety by binding to GnRH-R in tumors, thus specifically delivering (targeting) the cytotoxic drug to tumor cells. At the level of tumor cells, the bioconjugate is internalized and degraded at the lysosomal level; in this way the anticancer drug is specifically released into the tumor cells to exert its cytotoxic effects, while sparing normal cells. In conclusion, GnRH-R are expressed not only at the pituitary level but also in a wide range of tumor tissues; these receptors are at present under investigation as an effective molecular target for the development of novel therapeutic strategies.

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