The combination of testosterone-blocking drugs improves survival rates for men with prostate cancer, but managing their cardiovascular side effects is crucial.
By Robert H. Shmerling, MD, Senior Faculty Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing
Cancer treatment often involves tough trade-offs, and this is true for testosterone-blocking drugs used in prostate cancer treatment. These drugs function in two primary ways. Androgen deprivation therapies (ADT) halt the body’s testosterone production, a hormone that promotes prostate cancer growth. Another class of drugs, androgen-receptor signaling inhibitors (ARSIs), prevents testosterone from binding to its cell receptor.
ADT can slow or control prostate cancer, and increasing evidence suggests that adding ARSIs can further improve survival in advanced stages of the disease. This combined approach is known as intensified ADT. Researchers are also testing intensified ADT for some men with early-stage prostate cancer.
However, all testosterone-blocking drugs come with significant side effects, including metabolic changes that can negatively impact cardiovascular health. In June, British researchers reported that cardiovascular risks are heightened when ADT and ARSIs are administered together. They concluded that men undergoing intensified ADT should be informed of these risks and monitored for heart disease signs before and after treatment.
Study Goals and Results
The conclusions were drawn from a systematic review of 24 clinical trials assessing ADT and ARSI treatments for prostate cancer, published between 2012 and 2024, involving a total of 22,166 men aged 63 to 77. Their diagnoses ranged from nonmetastatic cancer with aggressive features to metastatic prostate cancer unresponsive to ADT alone.
The review aimed to compare cardiac events, including hypertension, cardiac arrhythmias, blood clots, heart attacks, or strokes, between ADT and intensified ADT.
Results indicated that adding an ARSI to ADT roughly doubles the risk of cardiac events across all prostate cancer stages. The risk for severe “grade 3” events, which may require hospitalization, ranged from 7.8% to 15.6%. Notably, using two ARSIs—abiraterone acetate and enzalutamide—resulted in a fourfold increase in cardiac risk. Evidence shows that combining these two drugs worsens side effects without enhancing prostate cancer survival, leading expert groups worldwide to discourage their combined use.
The study’s authors stress that intensified therapy poses higher risks for men with pre-existing cardiac conditions than for healthier individuals. In an accompanying editorial, Dr. Katelyn Atkins, a radiation oncologist at Cedars-Sinai Medical Center, noted that cardiovascular disease is the second leading cause of death among men with prostate cancer.
Candidates for traditional or intensified ADT should be evaluated for atherosclerosis, which involves fatty plaques in coronary arteries that can accumulate without symptoms. Fortunately, cardiac risk factors can be managed by lowering blood pressure, following a heart-healthy diet, exercising, and in some cases, using cholesterol-lowering drugs like statins.
Expert Opinions
“Research shows that intensive therapy prolongs survival and may even cure some men,” said Dr. David Crawford, head of urologic oncology at the University of Colorado Anschutz Medical Campus, who was not involved in the study. “Effective cancer treatment often involves combining drugs. However, we must address the cardiovascular side effects of ADT. Men who maintain a healthy weight, exercise, build muscle mass, and keep normal lipid and blood pressure levels fare better than those who gain weight and have many cardiovascular risk factors.”
“This study underscores the need to prioritize a patient’s cardiovascular history when making treatment decisions,” 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. “While intensifying treatment by adding multiple drugs earlier in prostate cancer management can be beneficial, it must be done cautiously. Physicians should consider and discuss pre-existing risk factors and how to mitigate them when planning treatment. The ARSI class of drugs has significantly improved outcomes, but the goal is to maximize benefits while minimizing side effects.”