Pei-Chun McGregor, MD, discusses where future research with androgen deprivation therapy-associated adverse events is headed, and called for multidisciplinary care for patients receiving this approach.
Pei-Chun McGregor, MD
Although the data may be confusing, there appears to be a link between androgen deprivation therapy (ADT) and cardiac complications, said Pei-Chun McGregor, MD, and healthcare professionals across disciplines need to ensure that they are aware of the adverse events (AEs) associated with the treatment.
The ultimate goal of ADT is to suppress testosterone levels, as testosterone causes malignant cells to grow. However, there are several AEs associated with this approach, including but not limited to hot flashes, muscle wasting, anemia, fatigue, cognitive impairment, loss of libido, erectile dysfunction, and development of subcutaneous fat.
“The most concerning AE is really the development of metabolic syndrome,” said McGregor. “Specifically, insulin resistance and dyslipidemia, which are key risk factors for cardiovascular disease.”
In an interview during the 2019 OncLive® State of the Science Summit™, McGregor, cardio-oncologist and director of Ambulatory Cardiology at VA Boston Healthcare System, instructor in medicine, Brigham and Women’s Hospital, shared efforts being made to increase awareness of ADT-associated cardiac complications in prostate cancer, discussed where future research is headed, and called for multidisciplinary care for patients receiving this approach.
OncLive: Could you discuss the role of ADT in prostate cancer?
McGregor: The underlying goal of ADT is essentially to suppress testosterone levels, as we know that testosterone is bad in prostate cancer; it makes malignant cells grow. We can suppress those levels whether that's through GnRH antagonists/agonists or through newer agents, such as the CYP17 inhibitors or the antiandrogens—however we can get those testosterone levels down or block those receptors. The hope is that we can ameliorate or attenuate the malignant cells from growing [through these efforts].
What are the key toxicities observed with ADT?
I've heard this term and I love it: [ADT] is basically chemically-induced menopause. That means [patients experience] all the great things that come with menopause, which include loss of libido. Unfortunately for men, [this means] erectile dysfunction, hot flashes—many patients will experience that—muscle wasting, development of subcutaneous fat, anemia, fatigue, and cognitive impairment.
What data address the potential link between cardiac complications and ADT?
If you look at all the trials, they're rather confusing. Most of the data are from observational and retrospective studies suggesting that there potentially could be link [between cardiac complications and ADT]. There's the VA trial, which looked at over 37,000 patients, and showed that the GnRH agonist group experienced significant effects on the cardiovascular system. [That group had] increasing risks for not just heart disease, but more specifically, the rates of heart attacks, strokes, and sudden cardiac death.
Again, [a lot of these data] are [from] post-hoc analyses; there is no randomized control trial that specifically is looking at cardiovascular disease as an endpoint. Most of them are from Europe—the negative ones—which really don't show that clear link between heart disease and ADT. The data might be kind of confusing for some people, but our government has taken it seriously—the FDA, as well as the European Medicines Agency. They have advocated for a label change saying that there possibly is a link. Also, if you look at the 2010 American Heart Association guideline along with the American Cancer Society [guideline], they came out basically saying, "Look, yes. The data are confusing, but we think probably there is a link, at least from everything that we have so far.'"
Could you expand on efforts being made to address this issue?
It’s great that the guidelines are gathering together; [it’s good to have] at least some guidance for the community doctors out there. There is that awareness. We are in a position to advertise this to folks who may not be aware that ADT does have some association with cardiovascular disease. If you talk to most internists, they would not know that ADT [can cause] adverse changes metabolically, and they might not be checking lipids or blood pressure.
Even for cardiologists, many of us don't know, and some of the medications that are used to block testosterone have also been shown to increase their QT; if [a patient’s] QT is increased, then [they’re] at risk for arrhythmias, which means [they] can potentially die from an abnormal heart rhythm. It’s about bringing awareness to the community. Guidelines are spearheading that. That's great, but we in this specialty and in the community, for example, OncLive is a great [platform] to get the message out.
What is the hope for the phase IIb PRONOUNCE trial?
This trial is still ongoing, but it is due to complete within the next year or 2. It's a multicenter, randomized control trial looking specifically at—and this is great, because this is actually finally looking at—cardiovascular events in patients with prostate cancer and also underlying pre-existing cardiovascular disease.
What they're planning on doing is randomizing patients into 2 arms: the GnRH antagonist arm—degarelix (Firmagon), specifically—and the agonist arm using leuprolide. [Investigators] plan to enroll around 900 patients and the primary endpoint is time from randomization to the first major adverse cardiovascular event (MACE). With the secondary endpoints, they're looking at individual MACE endpoints. Very interestingly, from this trial, they are also looking at biomarkers—cardiovascular, inflammatory, and immune biomarkers—so that will be very telling. It's the first trial to prospectively study this, so we'll finally learn whether GnRH agonists have that potentially adverse signal toward the cardiovascular system over the antagonists. It will be very exciting.
What are some other unanswered questions that still need to be addressed?
Honestly, a whole lot. We are still not sure about the role of stress testing in patients who already have heart disease. Is there a benefit? Is there a benefit if they were to have chest pain? There is a retrospective study from Dana-Farber Cancer Institute that looked at that; it showed that there's a potential mortality benefit in that population, but retrospective data have limitations; you have selection bias, etc.
Therefore, there's a whole lot that we still don't know unfortunately. [We have] newer agents coming on board, [such as] abiraterone acetate (Zytiga), which is showing potentially some signal that it is not great for the heart. Enzalutamide (Xtandi) may be okay, but enzalutamide and the newer antiandrogens have a lot of drug-drug interaction that we, as cardiologists, don't like. That’s all going to play a huge role in terms of managing patients with heart disease.
Where do you see future research headed?
The future must involve prospective data. We have a whole lot of retrospective, observational studies, which is great, as they are hypothesis-generating. However, we need to focus on a prospective way of looking at these events and incorporating newer techniques. I'm also an echocardiographer, and we have [a technique where we] look at a heart where we normally can't tell with our eyes, but the computer says “Hey, there's something abnormal with this heart. Let's treat this [patient] a little more aggressively than if we were to look at another [patient whose] heart is completely normal.” Just using technology would be a novel way of going about picking out who is at the highest risk.
What is your take-home message to your colleagues working in this space?
Bottom line is that ADT is not benign. We do need to watch out for its AEs, specifically the metabolic disturbances that we just talked about. Furthermore, with the newer drugs coming out, there are potential drug-drug interactions [to look out for]. It's important that if [healthcare professionals] don't know about [this issue] to seek out consultation from a cardio-oncologist, such as myself. The whole field of medicine is really approaching a more multidisciplinary kind of care. It's no longer, “I'm in my own little box. I'm a heart doctor, I only look at the heart and that's it.” We really need to treat the patient wholly.