Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I am so thrilled to have here with me today, a friend and colleague, Dr. Matthew Smith, who is a Professor of Medicine at Harvard Medical School and the Director of the GU group, as well as being a GU medical oncologist at Massachusetts General Hospital. Dr. Smith will talk with us today about the cardiovascular risks associated with androgen deprivation therapy in men with prostate cancer. Thank you so much for your presentation and for being here today, Dr. Smith.

Matthew Smith: Thank you, Dr. Morgans. So today I'll be describing the relationships between androgen deprivation therapy with GnRH agonists and risks for cardiovascular disease. And as a framework for my discussion, I'm going to really focus on guidance from the American Heart Association. In 2010, a science advisory from the American Heart Association, American Cancer Society, and American Urological Association reported on the relationship between androgen deprivation therapy in men with prostate cancer and risks for cardiovascular disease. That advisory concluded that ADT adversely affects some traditional cardiovascular disease risk factors including serum lipoproteins, insulin, sensitivity, and obesity and that some, but not all studies, have reported a relationship between ADT and greater risk for cardiovascular disease. The advisory also noted that most studies had reported no relationship between ADT and greater cardiovascular death. Taken together, these observations led to the conclusion that there may be a causal relationship between ADT and cardiovascular disease risk.

Later in 2010, the US Food and Drug Administration notified the manufacturers of gonadotropin-releasing hormone agonists, or GnRH agonists, of the need to add new safety information to the warning and precaution sections of their drug labels. This new information was to warn about increased risks of diabetes and certain cardiovascular disease in men receiving these medications for the treatment of prostate cancer. FDA's notification to manufacturers was based on its review of seven published studies, including a report by Dr. Nancy Keating in 2006, the first report of a relationship between ADT with GnRH agonists and greater risks for diabetes and cardiovascular disease. More about that study later.

Here's an example of the results of that FDA notification. This is a current Lupron Depot® package insert the language required by the FDA is exemplified here. It includes, "Increased risk of developing myocardial infarction, sudden cardiac death, and stroke has been reported in association with the use of GnRH agonists in men. The risk appears low based on the reported odds ratios and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonists should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice."

The science advisor from the American Heart Association nicely summarized why a relationship between ADT and cardiovascular disease may be plausible. They reported the effects of ADT on traditional cardiovascular disease risk factors. And for the most part, these observations came from prospective clinical trials of GnRH agonists in men with prostate cancer. ADT with GnRH agonists is associated with increased fat mass, primarily accumulation of subcutaneous fat, decreased insulin sensitivity, a marker of development of diabetes, and increase HDL cholesterol, LDL cholesterol, and triglycerides, as well as increased arterial stiffness. Notably prospective clinical trials have not reported an effect of ADT on other traditional cardiovascular disease risk factors, including blood pressure, waist-hip ratio, or inflammatory biomarkers.

With that information about the potential effect of ADT on cardiovascular risk and potential association with diabetes, Nancy Keating in 2006 reported the results of a large SEER-Medicare study to evaluate this relationship. Now, the power of this study is in its large size. It included more than 50,000 patient-years of follow-up in hundreds of informative events. In that study, Dr. Keating reported that androgen deprivation therapy with either a GnRH agonist or bilateral orchiectomy was associated with a significant increase in risk for incident or new diagnosis of diabetes with adjusted hazard ratios of 1.44 and 1.34, respectively. Using that same SEER-Medicare database, she observed that GnRH androgen deprivation therapy with the GnRH agonists was associated with a significant increase in incident coronary heart disease and myocardial infarction. Although the adjusted odds ratios were more modest at 1.16 and 1.11 respectively. Notably in this study, androgen deprivation therapy by bilateral orchiectomy was not associated with an increased risk of either coronary heart disease or myocardial infarction.

Now following the results of Dr. Keating's study, many subsequent studies attempted to evaluate the relationship between androgen deprivation therapy and cardiovascular and other adverse clinical outcomes that led to subsequent meta-analyses of those many clinical trials. And in 2010 in an American Heart Association journal, Atherosclerosis, Thrombosis, and Vascular Biology, a very nice meta-analysis was reported looking at both observational studies, as well as randomized controlled trials to evaluate these relationships. Now, the authors noted that meta-analyses of observational studies have reported associations between ADT and greater risks for cardiovascular disease and death with consistent associations for GnRH agonists in cardiovascular events and mixed associations for GnRH agonists in cardiovascular events. In contrast, meta-analyses of randomized control trials have not reported consistent associations between ADT in cardiovascular events or death.

And here's an example of a previously reported large meta-analysis. This was a big undertaking with more than 4,000 total patients in more than 500 informative events. And this study reported that ADT was not associated with increased cardiovascular mortality with a point estimate of relative risk of 0.93 in favor of androgen deprivation therapy. Now it is worth pointing out that these were randomized control trials designed for cancer outcomes, not cardiovascular events or mortality. And so these were really post hoc analyses of randomized control trials performed to look at cancer outcomes.

Now there are several possible explanation why the results of meta-analyses of randomized controlled trials and observational studies reach discordant conclusions. Randomized control trials may underestimate cardiovascular disease risk due to selection bias, typically accruing younger, healthier patients, and crossover to active treatment in the control group. Randomized control trials were designed and powered for cancer outcomes and may be insensitive for post hoc assessments of cardiovascular outcomes. Conversely, observational studies may overestimate cardiovascular disease risk due to confounding, including the potential issue of reverse causation and biases in reporting of cardiovascular outcomes.

In summary, androgen deprivation therapy adversely affects some cardiovascular disease risk factors, including serum lipoproteins, insulin sensitivity, and obesity. Meta-analyses of many observational studies have reported consistent associations between GnRH agonists and greater risk for cardiovascular events. In contrast, meta-analyses of randomized control trials designed for cancer outcomes have not reported consistent associations between GnRH agonists and cardiovascular events or deaths. Taken together, these observations suggest that there may be a causal relationship between GnRH agonists and greater cardiovascular disease. Thank you.