Testosterone-blocking drugs boost heart disease risk when given in combination

Cancer treatment can involve difficult tradeoffs, and that's also true of the testosterone-blocking drugs used in treating prostate cancer. These drugs work in two different ways. Androgen deprivation therapies (ADT) shut down the body's production of testosterone, a hormone that fuels prostate cancer growth. A newer class of drugs called androgen-receptor signaling inhibitors (ARSIs) block testosterone by deflecting the hormone from its cell receptor.

ADT can slow or control prostate cancer, and mounting evidence shows that adding ARSIs also improves survival when the disease is in advanced stages. This treatment combination is called intensified ADT. Researchers are now testing intensified ADT for some men with early-stage prostate cancer as well.

However, all drugs that block testosterone have challenging side effects, including metabolic changes that can compromise cardiovascular health. In June, British researchers reported that cardiovascular risks worsen when ADT and ARSIs are given together. The authors concluded that men who get intensified ADT should be counseled about the risks, and monitored for signs of heart disease before and after the treatment begins.

Study goals and results

The findings were derived from a systematic review of 24 clinical trials that assessed ADT and ARSI treatment for prostate cancer. Published between 2012 and 2024, the trials enrolled a combined total of 22,166 men ages 63 to 77. Their diagnoses ranged across the prostate cancer spectrum, from nonmetastatic cancer with aggressive features to metastatic prostate cancer that no longer responded to ADT by itself.

The goal of the systematic review was to compare ADT and intensified ADT with respect to cardiac events, including hypertension, cardiac arrhythmias (abnormal heartbeats), blood clots, or — in the worst case — heart attack or stroke.

Results showed that adding an ARSI to ADT approximately doubles the risk of a cardiac event across all prostate cancer states. Risks for severe "grade 3" events that can require hospitalization ranged between 7.8% and 15.6%. Notably, giving two ARSIs — abiraterone acetate and enzalutamide — led to a roughly fourfold increase in cardiac risk. Mounting evidence shows that combining abiraterone acetate and enzalutamide worsens side effects without improving prostate cancer survival. The use of that combination is now broadly discouraged by expert groups around the world.

The authors emphasize that intensified therapy is riskier for men with pre-existing cardiac conditions than it is for healthier men. In an accompanying editorial, Dr. Katelyn Atkins, a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles, noted that cardiovascular disease is the second leading cause of death among men with prostate cancer.

Candidates for traditional or intensified ADT, Dr. Atkins wrote, should be assessed for atherosclerosis, fatty plaques in coronary arteries that can accumulate asymptomatically. Fortunately, cardiac risk factors are treatable by lowering blood pressure, eating a heart-healthy diet, exercising, and in some cases using a cholesterol-lowering drug called a statin.

Experts comment

"More and more research shows that intensive therapy prolongs survival, and may in some men even evoke a cure," said Dr. David Crawford, head of urologic oncology at the University of Colorado Anschutz Medical Campus who was not involved in the study. "We have learned time and again from the treatment of many cancers that it is not one drug followed by another and another that results in the best outcomes. Rather, it is combining drugs more effectively to treat the cancer.

"Still, we need to tackle the challenges of prostate cancer treatment and focus on preventing cardiovascular events and other side effects of ADT. As clinicians and in clinical studies, we have seen that men who maintain their weight, exercise, expand muscle mass, and maintain normal lipids and blood pressure do much better than men who gain weight and have a lot of cardiovascular risk factors."

"This important study re-emphasizes the necessity to keep a patient's cardiovascular history front and center when treatment choices are made, " said Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor-in-chief of the Harvard Medical School Guide to Prostate Diseases.

"Intensification of treatment — that is, adding several drugs earlier and earlier in prostate cancer management — is to be both encouraged and cautioned. The caution is for physicians to consider and discuss pre-existing risk factors and how to modify them when deciding upon treatment programs. The ARSI class of drugs have greatly improved outcomes. The goal is to maximize the best outcomes while minimizing the side effects."