For decades, a fundamental strategy for treating advanced prostate cancer has been to block testosterone, a male-associated hormone (or androgen) that drives the growth and spread of the malignancy. This form of treatment, which is called androgen deprivation therapy (ADT), slows the cancer’s progression, but also causes side effects including weight gain, decreased muscle mass and fatigue. Now, concern is mounting about another complication of ADT: the increased risk of cardiovascular disease.
In 2021, the American Heart Association announced that cardiovascular disease has become a leading cause of morbidity and death in people with prostate cancer. This is partly a result of the success in treating the disease: the therapies available today, of which ADT is just one, allow some people with the cancer to live long enough to develop other, age-related conditions. But there is also troubling evidence that testosterone-suppressing drugs can increase the odds of adverse cardiovascular events, such as a heart attack or stroke, especially in people with pre-existing risk factors.
The growing focus on cardiovascular side effects is being driven, in part, by changes in how ADT is used. New, more powerful forms of the treatment are increasingly being deployed in combination with other testosterone-blocking drugs. And these are being administered at earlier stages of the disease. Although that approach seems to have survival benefits, “it also raises the prospect of cumulative and increased cardiovascular toxicity from ADT exposure”, says Vivek Narayan, a medical oncologist at the University of Pennsylvania in Philadelphia.
ADT is rooted in research from the 1940s showing that surgical removal of the testes — the main source of testosterone — slows prostate tumour growth. Surgical castration has major drawbacks, however. It is not only emotionally traumatizing, but also suppresses testosterone permanently, with lifelong metabolic consequences. So, when pharmacological alternatives became available in the 1980s, doctors were quick to adopt them.
In a healthy body, a fall in the levels of testosterone in the blood causes the brain’s hypothalamus to secrete gonadotrophin-releasing hormone (GnRH). This triggers the release of two other substances, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary gland. The two hormones work together to prompt the testes to secrete more testosterone. This chain of biochemical signalling maintains normal testosterone levels.
The first drugs developed to block testosterone release, called GnRH agonists, interrupt this system by a circuitous route. They upregulate FSH and LH, causing testosterone levels initially to surge. However, this eventually yields the opposite effect: the pituitary responds by shutting down FSH and LH secretion, and after a few weeks of treatment, testosterone levels plummet.
GnRH agonists opened the door to a new era of ADT, whereby testosterone levels could be suppressed temporarily and reversibly. “At first, we thought they were these wonderful drugs and the only side effect was hot flashes,” says E. David Crawford, a urologist at the University of California, San Diego. But, over time, Crawford says, other side effects — including cardiovascular problems — became evident. In 2010, with evidence linking ADT to heart disease growing stronger, the US Food and Drug Administration (FDA) ordered pharmaceutical companies to add a note to their drug labels warning that taking GnRH agonists for prostate cancer slightly increased the risk of heart attack, sudden cardiac death and stroke.
A possible alternative
Just how ADT elevates cardiovascular risk is unclear. Testosterone suppression is associated with adverse effects on lipids in the blood, insulin resistance, raised blood sugar levels, loss of muscle mass and abdominal weight gain — all of which are well-established cardiac risk factors. A disorder called metabolic syndrome, resulting from testosterone suppression, can increase the risk of heart attack and stroke over time. But Narayan points out that some people receiving ADT experience these cardiovascular events in the first year of treatment, which is a short time for medication-induced heart disease to develop and potentially turn lethal.
When these early events occur, other factors beyond metabolic syndrome might also play a part, Narayan says. ADT might exert direct effects on the functioning of endothelial cells lining the blood vessels, increase inflammation and affect other myocardial pathways in ways that worsen pre-existing — and potentially undiagnosed — heart conditions. “Maybe the risk from ADT is less about inducing new coronary artery disease than it is about making existing disease more unstable,” Narayan says.
There is some evidence that another form of androgen-depriving therapy, involving drugs called GnRH antagonists, is associated with a lower risk of cardiovascular problems than are GnRH agonists. These drugs block LH and FSH production without the initial surge that agonists provoke. Clinical-trial results published in 2020 suggested that a GnRH antagonist called relugolix approximately halved the risk of a major cardiovascular event occurring, compared with a GnRH agonist called leuprolide1. Only around 3% of 622 relugolix-treated men experienced such an event within 48 weeks of treatment, compared with just over 6% of 308 men treated with leuprolide.
However, the study’s main goal was not to assess cardiovascular risk, but to compare the drugs’ ability to suppress testosterone in individuals with recurrent prostate cancer. Cardiovascular events were considered solely during a sub-analysis. And this was not statistically strong enough to provide conclusive evidence about the effect of the two drugs on the risk of heart disease, according to the study’s lead author, Neal Shore, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina. “To definitively answer the question about differences in cardiovascular events between GnRH agonists and GnRH-receptor antagonists, prospective studies with cardiovascular events as the end point would be needed,” Shore says.
One such trial, launched in 2016 under the name PRONOUNCE, suggested that there was no difference in cardiovascular risk between the two drug classes2. The study was ended prematurely after failing to reach its recruitment target within four years, leaving uncertainty about its findings. However, a 2021 analysis of more than 32,000 people with prostate cancer who were treated with either of the same two drugs used in PRONOUNCE also found no difference in cardiac risk3. Timothy Lyon, a urologist at the Mayo Clinic in Jacksonville, Florida, and a co-author of the study, says those results bolster the PRONOUNCE trial’s findings with “evidence from routine clinical practice”. Moreover, nearly 20% of individuals treated in the study were Black, which is four times the number of Black or African American participants in PRONOUNCE. Black people are at higher risk of both developing prostate cancer and dying from it than are white people.
New forms of ADT are posing other cardiovascular challenges. Instead of blocking testosterone signalling pathways in the brain, these powerful second-generation treatments act directly on the hormone. Anti-androgens such as apalutamide, enzalutamide and darolutamide deflect testosterone from its cell receptor, and a drug called abiraterone prevents testosterone synthesis.
These agents were first introduced for prostate cancer treatment just over a decade ago. They were initially used only for cancer that had spread beyond the prostate and was no longer responding to GnRH-directed drugs. But regulators at the FDA and other agencies worldwide have since made them available for treating earlier stages of the disease, when front-line ADT is still working.
Clinical trials suggest that second-generation agents prolong overall survival and delay cancer progression, but evidence of their cardiovascular risks is also rising. Daniel Lenihan, a cardio-oncologist at Saint Francis Medical Center in Cape Girardeau, Missouri, says that the testosterone-synthesis blocker abiraterone worsens existing hypertension in people with prostate cancer. For some people, it leads to oedema in the legs (a possible sign of heart failure) or a drop in blood potassium levels that aggravates an underlying predisposition to developing an irregular heartbeat. “The ultimate goal with these second-generation therapies is to further reduce androgen levels, but we have to acknowledge that the human body is very complex,” Lenihan says. “If you target one area, another can be affected.”
Lenihan is founder of the International Cardio-Oncology Society in Tampa, Florida, which provides clinical training in the management of cardiovascular risks during cancer treatment. In a society webinar last November, 200 urologists from various countries who were surveyed by Lenihan said that fewer than one in ten people with prostate cancer are seen by a cardiologist before starting hormonal therapy. The goal should be to prevent cardiac complications, or at least to detect them before they develop into major events, he says. “But most of the time, a cardiologist is brought in only after a major cardiac event has already occurred.”
Jordan Ray, a cardio-oncologist and colleague of Lyon’s at the Mayo Clinic, agrees. The top predictor of cardiovascular problems with ADT is a history of heart disease. But Ray points out that many people have heart disorders that become apparent only after the treatments begin. Of particular concern is undiagnosed atherosclerosis. ADT can worsen this condition through immune-mediated pathways, Ray says, and increase the risk of an acute cardiac event.
Ray advises that any man who has at least one cardiovascular risk factor and is expected to receive more than six months of ADT should undergo a cardiac evaluation before starting treatment. Most of the time, he recommends lifestyle changes, such as a Mediterranean-style diet, smoking cessation and strength training to counteract muscle loss. Lenihan typically also recommends daily aspirin for people receiving ADT. “And if they have evidence of cardiovascular disease, then you want to treat more aggressively with a statin and advise about hypertension,” he says. “When we can mitigate cardiovascular impacts pre-emptively, then the outcomes are much better. Waiting until after an emergency happens is not productive.”