Are Prostate Cancer Drugs Safe for the Heart? Key Findings from the PRONOUNCE Trial

The PRONOUNCE trial, initiated in May 2016, set out to investigate the cardiovascular safety of two prominent drugs used in the treatment of prostate cancer. This study was conducted by an international team of urologists, oncologists, and cardiologists, with a focus on comparing the cardiovascular outcomes associated with two types of androgen deprivation therapy (ADT) drugs: leuprolide (Lupron), a luteinizing hormone-releasing hormone (LHRH) agonist, and degarelix, a gonadotropin-releasing hormone (GnRH) antagonist. The results of this trial have sparked discussions in the medical community regarding the cardiovascular safety of these therapies, as they remain a topic of considerable debate and uncertainty.

Understanding Androgen Deprivation Therapy (ADT) in Prostate Cancer Treatment

Prostate cancer is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Androgen deprivation therapy (ADT) is a cornerstone in the management of advanced prostate cancer. The rationale behind ADT is to reduce the levels of circulating androgens (such as testosterone), which fuel the growth of prostate cancer cells. ADT can be achieved through surgical castration or more commonly through pharmacological means, involving LHRH agonists, GnRH antagonists, or antiandrogens.

1. LHRH Agonists (e.g., Leuprolide/Lupron): LHRH agonists, such as leuprolide (Lupron), initially stimulate the release of luteinizing hormone (LH) from the pituitary gland, leading to a temporary surge in testosterone levels (known as a "flare") before downregulating the pituitary receptors and ultimately reducing testosterone production to castration levels. This method has been widely used but is associated with several potential adverse effects, particularly concerning cardiovascular health.
2. GnRH Antagonists (e.g., Degarelix): GnRH antagonists like degarelix work differently from LHRH agonists. They directly block the GnRH receptors in the pituitary gland, leading to an immediate reduction in LH and follicle-stimulating hormone (FSH) levels without the initial testosterone surge. This mechanism theoretically reduces the risk of flare-associated complications and has been hypothesized to have a safer cardiovascular profile compared to LHRH agonists.

The Need for the PRONOUNCE Trial

Prior to the PRONOUNCE trial, several studies had suggested a potential association between ADT and an increased risk of cardiovascular events, especially in patients with preexisting cardiovascular conditions. However, the data were conflicting and often derived from retrospective analyses or observational studies with inherent biases. There was a clear need for a robust, prospective, randomized clinical trial to definitively compare the cardiovascular safety profiles of LHRH agonists and GnRH antagonists. This led to the development of the PRONOUNCE trial, which was designed to address this gap in clinical knowledge.

PRONOUNCE Trial: Study Design and Objectives

The PRONOUNCE trial was a prospective, multicenter, randomized, open-label Phase IIIb trial that enrolled patients with prostate cancer who were at increased risk of cardiovascular disease. The study aimed to compare the incidence of major adverse cardiovascular events (MACE) between patients treated with leuprolide (Lupron) and those treated with degarelix.

• Primary Objective: The primary endpoint was the time to first occurrence of a MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke within 12 months of initiating therapy.
• Secondary Objectives: These included overall survival, prostate cancer-specific survival, biochemical recurrence, and other cardiovascular outcomes such as heart failure, arrhythmias, and thromboembolic events.

Key Findings and Implications for Cardiovascular Safety

Despite its well-intended design and the collaboration of specialists across disciplines, the PRONOUNCE trial faced several challenges and ultimately failed to meet its primary endpoint due to premature termination. The study was halted early because of slower-than-expected enrollment rates, which limited its statistical power to detect a significant difference between the two groups. However, the available data provided some insights into the cardiovascular safety profiles of LHRH agonists and GnRH antagonists.

1. Findings for Leuprolide (Lupron):
   • The patients treated with leuprolide showed a trend toward higher rates of cardiovascular events compared to those treated with degarelix. This finding aligns with previous observational studies that have suggested an association between LHRH agonists and increased cardiovascular risk.
   • The initial surge in testosterone levels caused by LHRH agonists may contribute to the destabilization of atherosclerotic plaques, potentially leading to adverse cardiovascular events, especially in high-risk populations.
2. Findings for Degarelix:
   • Degarelix, by directly blocking the GnRH receptors, avoids the initial testosterone flare and provides a more immediate and stable suppression of testosterone. This mechanism of action was hypothesized to reduce the risk of cardiovascular events, particularly in patients with preexisting cardiovascular disease.
   • Although the PRONOUNCE trial did not demonstrate a statistically significant reduction in MACE with degarelix, the numerical trend in favor of degarelix suggests a potential cardiovascular benefit that warrants further investigation in adequately powered studies.

Broader Context: Cardiovascular Risks Associated with ADT

Cardiovascular risk remains a critical concern for prostate cancer patients undergoing ADT, especially since these patients are often older and may have comorbidities such as hypertension, diabetes, or a history of cardiac disease. The mechanisms by which ADT may increase cardiovascular risk are multifactorial:

• Endothelial Dysfunction and Atherosclerosis: ADT has been linked to metabolic changes that can lead to insulin resistance, hyperlipidemia, and increased visceral fat, all of which contribute to endothelial dysfunction and atherosclerosis.
• Prothrombotic State: Hormonal changes induced by ADT can promote a prothrombotic state, increasing the risk of thromboembolic events.
• QT Interval Prolongation: Both LHRH agonists and GnRH antagonists can potentially prolong the QT interval, which could predispose patients to arrhythmias.

Clinical Implications and Recommendations for Practice

Given the uncertain cardiovascular safety profile of prostate cancer drugs like leuprolide and degarelix, healthcare professionals should adopt a personalized approach when considering ADT for their patients. Several recommendations can be drawn from the current evidence base:

1. Assessment of Baseline Cardiovascular Risk: Before initiating ADT, a thorough cardiovascular risk assessment should be performed. This includes evaluating the patient's history of heart disease, hypertension, diabetes, lipid profile, and lifestyle factors.
2. Choice of ADT Based on Cardiovascular Risk: For patients with high baseline cardiovascular risk, GnRH antagonists like degarelix may be preferred over LHRH agonists, given the theoretical benefit of avoiding the initial testosterone flare and its associated risks.
3. Multidisciplinary Collaboration: The management of prostate cancer patients on ADT requires collaboration between urologists, oncologists, and cardiologists to optimize both oncologic and cardiovascular outcomes.
4. Monitoring and Management of Cardiovascular Health: Patients on ADT should be regularly monitored for cardiovascular risk factors and symptoms. Interventions such as lifestyle modification, statin therapy, antihypertensive medications, and antiplatelet agents may be considered as part of a comprehensive cardiovascular risk management strategy.
5. Informed Decision-Making: Patients should be informed of the potential cardiovascular risks associated with ADT, and the decision to initiate therapy should be a shared one, taking into account the patient's preferences, overall health, and cancer prognosis.

The Need for Further Research

While the PRONOUNCE trial has provided valuable insights, it has also highlighted the need for further research to clarify the cardiovascular safety profiles of different ADT options. Future trials should aim to include larger patient populations, longer follow-up periods, and more diverse patient groups to provide a clearer understanding of the risks and benefits associated with these therapies.

Conclusion

The PRONOUNCE trial has underscored the ongoing uncertainty regarding the cardiovascular safety of prostate cancer drugs like leuprolide (Lupron) and degarelix. While some data suggest a potential advantage for GnRH antagonists in reducing cardiovascular risk, the evidence remains inconclusive. Healthcare professionals must remain vigilant in assessing cardiovascular risk in their prostate cancer patients and should consider a multidisciplinary approach to manage these risks effectively. Further research is needed to provide more definitive guidance on the safest and most effective strategies for managing prostate cancer while minimizing cardiovascular harm.