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Luteinizing hormone-releasing hormone (LHRH) antagonists were hailed as a potential solution to the cardiovascular toxicity associated with androgen-deprivation therapy (ADT), but that enthusiasm may have been premature, said authors of a recent "Comments & Controversies" article in the

Meta-analyses of past clinical trials and real-world observational studies have been poorly designed and conflicting, and most recently, a well-designed phase III randomized clinical trial did not show a cardiovascular benefit associated with LHRH antagonists versus agonists, said Tamim Niazi, MD, of McGill University in Montreal, Quebec, and colleagues.

In the article they reviewed all the available data, including results of the study, which they called the best-designed phase III clinical trial to date comparing cardiovascular outcomes with LHRH antagonists versus agonists in men with prostate cancer.

"Although there may be advantages of antagonists in terms of speed of testosterone decline and avoiding testosterone surge, given the conflicting findings and limitations of available studies, cardiovascular risk reduction cannot solely justify the use of LHRH antagonists in prostate cancer patients with pre-existing cardiovascular disease," the team concluded.

In the following interview, Marwan Tolba, MD, of Dalhousie University in Halifax, Nova Scotia, discussed the clinical data and offered advice on managing patients at cardiovascular risk.

The HERO trial reported a cardiovascular benefit with an antagonist versus an agonist. But you noted some problems with this study. What were they?

Tolba: The multinational Phase III randomized conducted by [Neal] Shore et al. is a very important trial that compared the new oral antagonist relugolix versus the LHRH agonist leuprolide. A total of 622 patients were enrolled in the trial. However, in the HERO trial, major adverse cardiovascular events [MACE] such as myocardial infarction, heart failure, stroke, and cardiovascular death were not pre-specified as outcomes of interest in the study, were defined on [Medical Dictionary for Regulatory Activities]-coded adverse events, and were not independently verified or adjudicated. These limitations remain, in addition to the open-label design that might be a risk of bias.

The PRONOUNCE trial is the best trial to date examining this issue. Why is that?

Tolba: The reasons behind this are that it's the first international, phase III randomized clinical trial -- high level of evidence -- to prospectively compare the cardiovascular safety of a GnRH [gonadotropin-releasing hormone] antagonist and a GnRH agonist in patients with prostate cancer.

In essence, the trial was designed with a primary endpoint to definitely answer this dilemma. What's more, the authors tried to address or minimize most biases criticized in other trials, which further enhanced the quality of these data. The study endpoints were centrally adjudicated, and analysis was blinded. In this study, all patients had pre-existing atherosclerotic CV [cardiovascular] disease, and cardiology follow-up was encouraged.

Despite that, the trial was terminated early due to low accrual and an overall low number of events. The results demonstrated that there was no difference in the rate of MACE between antagonist and agonist at 12 months. Similarly, secondary endpoints -- all-cause death, myocardial infarction, and stroke -- were not different between antagonist and agonist.

Interestingly, the results of the study confirmed the hypothesis that the CV morbidity of LHRH agonists may have been overrated given the considerably lower than anticipated MACE rate in the agonist arm. The 12-month event rate was low at 5.5% for the antagonist, degarelix (D) vs 4.1% for the agonist, leuprolide (L); all-cause death: 2.9% (D) vs 3.3% (L); MI 1.8% (D) vs 1.1% (L) and stroke: 1.1% (D) vs 1.1% (L).

Although some advocates may consider the results of PRONOUNCE to be suboptimal because of its limitations, in our opinion, even with full accrual and longer follow-up, it is unlikely that there would eventually be a significant difference between the arms, given the reported low rates of CVE [cardiovascular events] with both agonists and antagonists.

Although the CV outcome in PRONOUNCE contrasts sharply with the findings of HERO, we feel that the results of PRONOUNCE are closer to the truth, given that PRONOUNCE was primarily designed to ascertain CVE through central adjudication and was ideally conceived to isolate results from confounders and biases.

Do you have any advice on how to best manage a patient with prostate cancer and cardiovascular disease risk or history?

Tolba: Optimal CV management of men with a history of CVE should be addressed, ideally before initiation of ADT, without compromising the promptness of their oncologic care. Initial communication with the family doctor and cardiologist for assessment of the cardiovascular risk factors in higher-risk men to prevent or decrease risks of future heart disease is important. Specialists should follow available guidelines to mitigate the risks in high-risk patients, like healthy diet and regular physical activity advice and promotion.

Additionally, inform patients of the possible increased risk of CVD, and the importance of controlling their blood pressure, weight, lipid profile, and keeping their blood sugar monitored with their GPs or family doctors.

Is there anything else you want to make sure oncologists understand about this issue?

Tolba: Many studies have looked into both drugs to ascertain their efficacy and toxicity. However, there remains a lack of consensus, particularly with newly emerging studies, on the severity of CV toxicity and the impact on patients' outcomes

The role of CVD prevention in prostate cancer patients on ADT is being thoroughly evaluated through the trial, which is composed of two studies to identify the development of cardiovascular risk factors in these patients, particularly when on ADT. Initial have already been published and found that a significant percentage of prostate cancer patients are having CV risk factors. The trial is trying to further investigate if modifying CV risk factors through medication and lifestyle changes can have an improved cardiovascular-related outcome in prostate cancer patients.

Read the article here and expert commentary about it here.