Introduction:

Gonadotropin-releasing hormone (GnRH) antagonists have been postulated to result in fewer major adverse cardiovascular events (MACE) than luteinizing hormone-releasing hormone (LHRH) agonists due to a lack of follicle-stimulating hormone (FSH) flare. Although relugolix yielded lower MACE than leuprolide in the HERO trial, the randomized prospective PRONOUNCE trial did not find a difference in MACE between degarelix and leuprolide. Additionally, a meta-analysis assessing the differential impact of LHRH agonists and antagonists on clinical safety and oncologic outcomes reported that antagonist use was associated with lower overall mortality rates than agonists (Risk Ratio=0.48, 95% CI 0.26-0.90, p=0.02). Due to patient selection, MACE and mortality outcomes for LHRH agonists and antagonists in highly selected clinical trial populations may differ from those in daily practice. This real-world data study compares MACE and mortality risk for PCa patients treated with LHRH agonists to those who received an antagonist.

Methods:

Analyses of data from the Decision Resources Group, which covered the majority of entities in the US healthcare system, including >300 million patients’ medical and pharmacy claims and electronic health record data, were conducted to evaluate MACE and all-cause mortality incidence after ADT initiation. The analysis set included PCa patients who received at least 1 injection of ADT between 1991-2020 (99% of patients started ADT within 2010-2020). Patients who took both an agonist and antagonist and those with MACE <6 months prior to ADT start were excluded. MACE was defined as myocardial infarction, stroke, and mortality from any cause. Kaplan-Meier event-free survival curves and Cox regression compared MACE and all-cause mortality risk between patients on agonists vs. antagonist. The multivariate regression model took into account variables associated with increased MACE risk including: age, treatment setting, baseline metastasis, personal MACE history, BMI, ADT drug type (full list in Fig. footnotes).

Results:

Median age was 75 years. 12.7 and 1.3% of patients were Black and Asian, respectively. Proportions of patients with MACE history were balanced between the agonist and antagonist groups (3.0 vs. 3.4%). MACE occurred in 7,681 patients after ADT start. Overall, MACE incidence was 3.9% and 19.6% at 1 and 4 years after ADT initiation, respectively. In White, Black, and Asian patients, MACE incidence was 4.0 vs. 2.4 vs. 2.2%, respectively, at 1 year after ADT initiation and 21.0 vs. 13.3 vs. 11.7%, respectively, at 4 years. Both unadjusted (HR=1.5, 95% CI 1.4-1.7, p<0.001) and adjusted (HR=1.6, 95% CI 1.2-2.1, p<0.001) MACE incidences were higher for antagonist vs. agonists. Overall, mortality risk was 2.6% and 17% at 1 and 4 years after ADT initiation, respectively. Both unadjusted (HR=1.6, 95% CI 1.4-1.8, p<0.001) and adjusted (HR=1.8, 95% CI 1.3-2.4, p<0.001) mortality risks were higher for antagonist vs. agonists.

Conclusion:

In this real-world claims database, overall MACE and mortality risk both increased consistently by 4-5% per year during the first 4 years after ADT initiation. Patients with PCa who were treated with GnRH antagonist experienced more MACE and higher mortality compared to patients treated with LHRH agonist therapy. Our analysis of data from ~45,000 PCa patients collected over the most recent decade likely reflects real-world outcome patterns. As patients initiating ADT likely have a high burden of underassessed and untreated CV risk factors, clinicians should focus on monitoring and treating comorbidities to reduce mortality risk in PCa patients on ADT. Detailed studies evaluating time trends and predictive CV risk factors as well as mechanisms of MACE are needed to explain differences in relative risk for GnRH antagonists vs. LHRH agonists given the conflicting data from published prospective trials.

Funding: Tolmar Inc.