Cardiovascular Disease + Prostate Cancer

Dr. Pedro Barata is an Assistant Professor of Medicine at the Tulane Cancer Center. He’s keenly interested in genitourinary tumors with a particular focus on clinical trials.

Prostatepedia spoke with him recently about the intersection between cardiovascular disease and prostate cancer.

Not a member? Join us to read the rest of this month’s conversations about heart health and prostate cancer.

Why do we even talk about cardiovascular disease when it comes to prostate cancer? It doesn’t come up with lung cancer, so why does it in prostate?

Dr. Pedro Barata: When we think about cardiovascular events, it’s actually a growing topic in this field. As treatments get better and better, patients live longer. Some develop cardiovascular events because they just live long enough to experience those long-term toxicities.

In regard to prostate cancer, it’s usually in relation with hormonal therapy. For context, prostate cancer is a hormonally driven disease, and so its tumor growth depends on androgens. We’ve been using surgical castration or androgen deprivation therapy (ADT) to treat men with prostate cancer for several decades. We have been doing this to treat prostate cancer since the guys who discovered this got a Nobel Prize for it in the 60s. There’s a clearer connection between cardiovascular disease and ADT.

Explanations for this increased risk include metabolic changes, such as hyperglycemia, or dyslipidemia, and factors in relation with arteriosclerosis. This has been an ongoing discussion, to determine why ADT is correlated with increased risk for a cardiovascular event and what we can do to prevent that. We use ADT in localized disease combined with radiation therapy. We use it in the biochemical recurrence space. We use it in the advanced setting. And we also have other therapies called novel androgen inhibitors, such as abiraterone or enzalutamide, to explore this pathway. All of these hormonal manipulations give an increased risk for cardiovascular events.

On the other hand, there’s radiation, which is not a strong risk factor in prostate. In the majority of the cases, we end up not irradiating the chest, and so you don’t have an increased risk for cardiovascular events as compared with lung cancer or breast cancer where radiation is given to the chest, especially to the left side where the heart is. So, the risk for cardiovascular disease is mainly in ADT, novel androgen therapies, androgen pathway inhibitors, and chemotherapy to a much lesser extent.

What would you say to a man who’s reading this and doesn’t already have preexisting cardiovascular disease but has been prescribed ADT?

Dr. Barata: The risk is different depending on the patient. It is different when you have someone who already has preexisting cardiovascular risk factors such as high blood pressure or diabetes, for instance. Because we need to use ADT to suppress testosterone levels, the advice is always to go back and control cardiovascular risk factors in the best way possible. That usually includes getting the primary care physician involved in the care. He should have good blood pressure control, good diabetic or glycemic control, and he should focus on diet and exercise. Those are the factors that we can act on, and we can reduce or minimize the increased risks caused by treatment.

So you could address things as they come up?

Dr. Barata: Exactly. In the clinic on a day-to-day basis, apart from talking about prostate cancer, we talk about which risk factors are present, which are not, and what we need to pay attention to. We usually talk about these five things: ADT, diet, bone health, exercise, and good control of cardiovascular factors.

Every time I see a patient who is at moderate or high risk for cardiovascular events, I usually engage a cardiologist with a focus on oncology. They calculate the risk in a more objective manner. When we are concerned about the treatments we’re considering and their cardiovascular risks, involving a cardio-oncologist is a good way of making sure we don’t miss anything.

There are some data, which are not very strong, that suggest that an antagonist has a lower risk compared with an agonist in causing cardiovascular events. This is not settled yet, but there is a large Phase III trial going on to answer the question. Right now, we don’t have a preference. If it turns out that an antagonist correlates with the lower risk for cardiovascular events, then we’ll change our practice, and we’ll start using the antagonist as the treatment of choice.

Do you know who’s running that trial?

Dr. Barata: The trial is called PRONOUNCE. The collaborators of the study are Memorial Sloan Kettering and Duke Institute, and it’s sponsored by a pharma company. It’s still open. It’s a trial comparing the cardiovascular safety of degarelix, which is the LHRH antagonist, versus leuprolide, which is the LHRH agonist, in patients with advanced prostate cancer and cardiovascular disease. (See Prostatepedia February 2019 for a discussion with Dr. Matthew Roe about this trial.)

I predict it might be closed soon because it’s been open to accrual since 2016. We hope to have a result in the next 24 months.

What about after ADT treatment?

Dr. Barata: Fortunately, we cure a lot of patients with prostate cancer. Every time we deliver a treatment that cures but increases the risk for cardiac events, we should let the patient know that their risk doesn’t go away.

Because we deliver hormones for a short period of time for prostate cancer, that’s not as important as it is for other cancers. In testicular cancer, for instance, we follow patients to make sure that we have cardiovascular risk factors under control. So it’s important that survivorship programs for prostate cancer be mindful of cardiovascular events.

Does the impact that ADT has on prostate cancer last even after the ADT has been stopped?

Dr. Barata: We don’t know. In the localized setting, the duration of ADT is relatively short. For instance, if you have intermediate risk prostate cancer, you usually deliver six months of hormones, and if you have a high-risk disease, you treat them for two to three years. We have no long-term data showing the long-term impact on cardiovascular events for patients treated with three years of hormones, where you suppress testosterone for three years. We do know that, if you have advanced prostate cancer, you are usually in a long-term ADT, meaning continuous suppression, and that can last for five or more years. That’s where there’s more data.

If a person has diabetes or a prior history of cardiovascular problems, their primary care physician should be engaged to make sure that, even though we are done with treatments, we are still paying attention to preventable cardiovascular risk factors, like blood pressure, exercise, and diet.

Do you have any advice for men either going into prostate cancer treatment or already undergoing treatment?

Dr. Barata: There’s frequent toxicity in patients diagnosed with GU tumors in general, and prostate cancer is more associated with ADT. Ask your treating physician about your specific risks. What can you do to prevent or minimize cardiovascular events in the future? Is there a role for a cardio-oncologist, a cardiologist with a focus on oncology, on your healthcare team?

Not a member? Join us to read the rest of this month’s conversations about heart health and prostate cancer.

Advertisement

February: Heart Health + Prostate Cancer

In February, Prostatepedia is talking about cardiovascular risk in prostate cancer patients. Dr. Charles Snuffy Myers frames the discussions for us.

“It turns out that the relationship is complex. Men with cardiovascular disease have a higher incidence of prostate cancer. This may, in part, be due to an impact of elevated cholesterol on prostate cancer progression. However, other factors may also be involved. For example, obesity is associated with an increased risk of cardiovascular disease and with progression of prostate cancer. Similarly, a diet rich in calories and meat is associated with an increase in insulin like growth factor 1 and this hormone has been linked to prostate cancer progression.

Removal of androgens, such as testosterone and dihydrotestosterone, plays a central role in the treatment of prostate cancer. In turn, low testosterone exacerbates insulin resistance, diabetes, visceral obesity and hypertension—known risk factors for cardiovascular disease.

In this issue, Dr. Pedro Barata from Tulane University gives us an overview of the issues at stake when we discuss prostate cancer and cardiovascular disease.

Dr. Michael Freeman from Cedars- Sinai discusses the evidence that cholesterol might drive progression in prostate cancer and the possibility that lowering cholesterol with statins might have a therapeutic impact. One of the more interesting observations he discusses is that certain gene expression patterns might lead to a increase or decrease in sensitivity to cholesterol levels.

Dr. Matthew Roe, a well known cardiologist from Duke University’s Clinical Research Institute (DCRI), speaks about the PRONOUNCE clinical trial he’s running. PRONOUNCE compares the cardiovascular safety of Firmagon (degarelix) versus Lupron (leuprolide) in men with advanced prostate cancer.

Dr. Darryl Leong from Canada’s McMaster University talks about his RADICAL-PC clinical trial, which evaluates the effectiveness of modifying cardiovascular and lifestyle risk factors in men who’ve just been diagnosed with prostate cancer.

Finally, Dr. Christina M. Dieli- Conwright talks about her clinical trial evaluating a 16-week program of cardiovascular and strength exercises in men with prostate cancer.”

Join us to read our February conversations about heart health + prostate cancer.

Join A Trial: Sipuleucel-T + Active Surveillance

Urologist Dr. Bruce Brown is the Chief Medical Officer of Dendreon, makers of the prostate cancer therapeutic vaccine PROVENGE (sipuleucel-T).

Prostatepedia spoke with Dr. Brown about a trial they’re running that will evaluate the effectiveness of sipuleucel-T in reducing disease progression in men on active surveillance.

What is the thinking behind your trial that looks at sipuleucel-T in men with lower risk non-metastatic prostate cancer?

Dr. Bruce Brown: As you know, PROVENGE, which is Dendreon’s product for metastatic castrate-resistant prostate cancer (mCRPC), has been approved since 2010. It’s been prescribed to over 30,000 men and has been found to be effective and safe. But that is in a small population of prostate cancer patients – men with metastatic disease that has spread and who have already failed some treatments. When we looked at the whole prostate cancer landscape, we asked how we can potentially get this treatment to more prostate cancer patients who may benefit?

In the United States, about 180,000 men a year are diagnosed with prostate cancer. Over 80% of those men have localized disease. That is much different than the current indication for PROVENGE. Of that 80%, more than 50,000 will go on active surveillance. Active surveillance is a treatment option for localized disease that hasn’t spread.

There are three main treatment options when you are diagnosed with localized prostate cancer. First is active surveillance, which we’ll discuss. There is also radical prostatectomy, which removes the prostate, and radiation therapy to the prostate as well as the tissue outside the prostate. Obviously, radiation therapy and radical prostatectomy have some side effects.

Active surveillance is exactly how it sounds. You “actively” monitor patients, meaning the cancer is not treated but closely observed. You repeat biopsies. You repeat blood tests. You repeat physical exams. The thought is that a lot of prostate cancer patients don’t progress and their disease doesn’t change: it doesn’t spread or metastasize. Their risk of dying of prostate cancer is fairly low. They might do just fine for years without the need for more aggressive treatments that may result in life-altering side effects.

We focused on this active surveillance population. Of men who go on active surveillance, about 10% a year will progress and go on to further treatment. We wondered if there was a way for sipuleucel-T to delay or prevent their disease from progressing and needing other treatments. They could go on sipuleucel-T and be spared the side effects of surgery or radiation therapy.

At a high level, that’s why we’re doing this particular trial. But what medical evidence did we have that our drug might be beneficial in this setting? We have several studies that looked at treating men with earlier-stage disease with sipuleucel-T. These studies weren’t in our labeled indication that we sell commercially. We have evidence that the immune response in men with earlier disease was even greater than in men with advanced disease. That gave us some inkling that the patient’s own immune system will mount a bigger response when sipuleucel-T is given earlier.

That makes sense because immunotherapies work best when the burden of tumor is lower, which would be the case in early stage disease. Immunotherapies also work better when a patient’s own immune system is more robust. Again, as you progress through any disease, especially cancer, your immune system is able to mount less and less of a response the further along you go. So we have evidence that our drug mounts more of an immune response in earlier disease.

We also did another trial where we gave sipuleucel-T to patients with localized disease. Two weeks after they received their last dose of sipuleucel-T we removed their prostate. Then we looked at those prostates and we saw that the immune cells had migrated into the prostate and surrounding tumor cells. It showed us that things were happening from our drug because that doesn’t happen in patients who don’t get our drug.

Again, our drug was causing the immune cells to start doing their work – moving to the tumor, and then hopefully at some point, although we didn’t see it in the trial because we didn’t follow them long enough, to start doing something to those tumor cells. It made us feel better about the fact that by treating patients with sipuleucel-T early, the immune cells would migrate to the tumor.

What can patients expect to happen during the trial?

Dr. Brown: We are looking for patients who have been diagnosed with prostate cancer within the last 12 months. We’re looking for certain patients that fit into roughly a low or intermediate risk category, based on their biopsy results. These patients don’t have spread of disease, but again, they may progress over the years. These are patients who have been newly diagnosed, whose biopsy fits these particular characteristics, and who are considering active surveillance and perhaps want to be on a treatment that doesn’t involve surgery or radiation therapy.

If a patient decides to enter this trial, he will be randomized. That means he will be put into one of two groups. We will enroll approximately 450 patients—two-thirds of the patients will be treated with a normal dose of sipuleucel-T, which is three treatments two weeks apart. One-third of the patients will not receive sipuleucel-T; they’ll continue to be followed per the active surveillance protocol.

Both groups of patients will follow predetermined study visit follow-ups, which involve blood tests, physical exams, and subsequent biopsies. Our primary endpoint is based on the follow-up biopsies, to see how many in each group have biopsies that get worse.

How long are you planning on following these men?

Dr. Brown: We will do the first biopsy between 12 and 18 months after they are randomized into the trial and then we’ll do a second biopsy between 33 and 39 months. Each patient will be followed for at least three years.

If someone who is reading this is interested in participating, who should he contact?

Dr. Brown: He can visit ClinicalTrials.gov or contact (800) 772-3125. When prompted, please enter study code number: 170101 (do not hit the #, hash or number key). Expect a brief silence until an available agent answers. In the event an agent is not readily available, you will be directed to a voicemail box.

Are there any associated fees?

Dr. Brown: No. Patients don’t pay anything to participate in the trial.

Not a member? Join us.