Kardiovaskuläres Risiko unter Androgendeprivationstherapie zur Behandlung des hormonabhängigen Prostatakarzinoms

Tschöpe, Carsten; Kherad, Behrouz; Spillmann, Frank; Schneider, C. A.; Pieske, Burkert; Krackhardt, Florian

doi:10.1007/s00059-016-4422-8

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…Observational, retrospective studies using real-world databases have shown that GnRH antagonists may have a better CV risk profile than GnRH agonists in patients with and without a history of CV events. [21][22][23][24] An overview of CV risk associated with the use of ADTs, specifically a comparison between a GnRH agonist and antagonist and between ADT use and non-ADT use, is provided in Table 5. Data from the Margel study 13 and the HERO study 14 showed that antagonists were associated with a several-fold lower risk of CV events than agonists.…”

Section: Discussionmentioning

confidence: 99%

“…It states that ADT for prostate cancer appears to increase the risk of cardiovascular events, although GnRH antagonists may be associated with a lower risk of CV events than GnRH agonists. The GnRH antagonists may have a lower risk of CV events compared with agonists, as evidenced from randomized controlled trials (RCTs), 13–15 meta‐analysis of data from prostate cancer trials with GnRH analogs, 16–20 and real‐world data, 21–24 although not all studies have been consistent in these findings (Table 1). 25–27 …”

Section: Risk In Rcts With Gnrh Agonists and Gnrh Antagonist Referenc...mentioning

confidence: 99%

“…12 It states that ADT for prostate cancer appears to increase the risk of cardiovascular events, although GnRH antagonists may be associated with a lower risk of CV events than GnRH agonists. The GnRH antagonists may have a lower risk of CV events compared with agonists, as evidenced from randomized controlled trials (RCTs), [13][14][15] meta-analysis of data from prostate cancer trials with GnRH analogs, [16][17][18][19][20] and real-world data, [21][22][23][24] although not all studies have been consistent in these findings (Table 1). [25][26][27] An injectable GnRH antagonist, degarelix, is available, but due to the relatively high rate of injection site reactions and a more frequent dosing schedule compared to GnRH agonists, there is still a medical need for additional treatment options which have a more favorable tolerability and CV safety profile with an acceptable dosing schedule.…”

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confidence: 99%

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A Model‐Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk

Sannala,

MacLean,

Larsen

et al. 2024

Clinical Pharm in Drug Dev

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Teverelix drug product (DP) is a parenteral gonadotropin‐releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone‐sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2‐compartment model with sequential first‐order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK–pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T < 0.5 ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360 mg SC and 180 mg IM with a maintenance dose of 360 mg SC 6‐weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

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Section: Discussionmentioning

confidence: 99%

Section: Risk In Rcts With Gnrh Agonists and Gnrh Antagonist Referenc...mentioning

confidence: 99%

mentioning

confidence: 99%

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A Model‐Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk

Sannala,

MacLean,

Larsen

et al. 2024

Clinical Pharm in Drug Dev

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“…ADT increases cardiovascular morbidity in men with PCa ( 16 ). Since the potentially different effects of GnRH agonists and antagonists on CVD risk are still controversially discussed ( 17 – 20 ), one aspect of this analysis was the comorbidity rate, in particular CVD comorbidity, among GnRH agonists and the antagonist. However, due to the small number of patients in the degarelix cohort, the results do not allow any conclusion and more evidence is needed.…”

Section: Discussionmentioning

confidence: 99%

Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes

Hupe

Hammerer

Ketz³

et al. 2018

Front. Oncol.

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Objective: The objective of this study was to obtain real-world information on gonadotropin-releasing hormone agonist/antagonist (GnRHa) therapy in patients with advanced prostate cancer (PCa).Materials and methods: Anonymized, routine healthcare claims data from approx. 75 German statutory health insurance funds from 2010–2015 (n = 4,205,227) were analyzed. Patients had an enrolment of 1 year before GnRHa, 1 index quarter of initial GnRHa prescription and ≥2 years of follow-up.Results: In total, 2,382 patients with PCa were eligible. The most frequent index therapy was leuprolide in 56.6%. The rank order of PCa comorbidity prevalence was consistent over time (% at index and 3-years of follow-up): hypertension (71.5; 85.0), hyperlipidemia (45.2; 60.8), cardiovascular disease (CVD) (35.7; 54.1), and diabetes (28.3; 36.2). Comparing pooled therapy classes (agonists, hybrids, and antagonist), no significant differences in the incidence of CVD or diabetes were observed. For hypertension, there was a significant increase for agonists (16.4%) compared to antagonists (6.9%, p = 0.022) and leuprolide hybrid group (11.6%, p = 0.006). During the follow-up period 23.9% of all PCa patients died. There were no significant differences concerning mortality rate and discontinuation rates between the cohorts. In total, 11.2% of all patients discontinued GnRHa after first prescription; the mean time to first switch to another GnRHa therapy was 100 days earlier for hybrids than for agonists (p = 0.016).Conclusion: This comparative retrospective analysis provides real-world information about healthcare characteristics and treatment patterns, highlighting the impact of different GnRHa on clinical outcomes for patients with advanced PCa in Germany.

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Is androgen deprivation therapy associated with cerebral infarction in patients with prostate cancer? A Korean nationwide population‐based propensity score matching study

et al. 2019

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Purpose Previous studies have suggested that androgen deprivation therapy (ADT) is associated with cerebral infarction. However, conflicting results have been reported by other researchers. The aim of this study was to evaluate the association between ADT and cerebral infarction in patients with prostate cancer (PC) using big data. Materials and Methods Using information from the National Health Insurance Service database representative of the entire Korean adult PC population (n = 206 735), data regarding ADT and cerebral infarction between 2009 and 2016 were analyzed. Adjusted hazard ratios for cerebral infarction associated with ADT were estimated using propensity score‐matched Cox proportional hazards models and Kaplan‐Meier survival analyses. Results The final cohort comprised 36 146 individuals with PC, including 24 069 men (66.6%) who underwent ADT. During the mean follow‐up of 4.1 years, 2792 patients were newly diagnosed with cerebral infarction. In the unmatched cohort, there was a significant difference in the annual incidence of cerebral infarction between the ADT and non‐ADT groups (22.8 vs 14.6 per 1000 person‐years, respectively). However, there was no significant difference between the ADT and non‐ADT groups in the matched cohort (14.9 vs 14.6 per 1000 person‐years). The adjusted hazard ratio for cerebral infarction for PC patients who underwent ADT was 1.045 (95% CI 0.943‐1.159; P = 0.401) compared with those who did not undergo ADT. In addition, the cumulative duration of ADT was also not associated with an increased risk for cerebral infarction. However, older age, hypertension, diabetes, myocardial infarction, congestive heart failure, peripheral vascular disease, renal disease, dementia, and atrial fibrillation were revealed to be factors contributing to cerebral infarction. Conclusion This nationwide population‐based study revealed that ADT was not associated with cerebral infarction after adjusting for potential confounders.

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Kardiovaskuläres Risiko unter Androgendeprivationstherapie zur Behandlung des hormonabhängigen Prostatakarzinoms

Abstract: Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

Cited by 7 publications

References 53 publications

A Model‐Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk

A Model‐Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk

Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes

Is androgen deprivation therapy associated with cerebral infarction in patients with prostate cancer? A Korean nationwide population‐based propensity score matching study

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