Falls rank among the top causes of death and injuries among the elderly, and the risk increases significantly in older people being treated for cancer. Now, investigators are reporting that a newer class of drugs for advanced prostate cancer is associated with a significant increase in fall risk.
Called androgen receptor inhibitors, or ARIs, these drugs target testosterone, a hormone that accelerates the growth of prostate tumors. Unlike traditional hormonal treatments that interfere with the body’s ability to make testosterone (known as androgen deprivation therapy, or ADT), ARIs work by preventing testosterone from binding to its receptor on cancer cells. Three ARIs were evaluated in the study — apalutamide, enzalutamide, and darolutamide — and each can limit prostate cancer progression and extend survival. The investigators emphasized that the benefits of using ARIs outweigh the risk of falls and fractures, which are rare even in treated patients.
What the investigators did
To generate the findings, the investigators performed a systematic review of previously published studies comparing ARI treatments with placebo. In all, 11 studies enrolling a combined total of 11,382 men met the criteria for evaluation. The average age of the men was 72, and the ARI treatments lasted between 5.4 and 20.5 months. Men were excluded if they had a prior history of heart disease or seizure disorders.
What they found
Results showed that 525 of 6,536 ARI-treated men (8%) had suffered falls, compared to 221 of 4,846 men (5%) who were given a placebo. Roughly half the falls in both groups resulted in fractures. However, grade-3 fractures causing more severe injuries occurred 1.6 times more frequently in the men taking ARIs. Apalutamide was associated with the highest fall risk (12%), followed by enzalutamide at 8% and darolutamide at 4.2%.
Just why ARIs boost fall risk isn’t known. Apalutamide and enzalutamide both cross the blood-brain barrier (making them useful for treating brain metastases), and may therefore have more central nervous system side effects that include falls. The drugs may weaken men by decreasing skeletal muscle mass and strength. The concurrent use of other drugs, such as benzodiazepines (including valium) or opioids, can also elevate the risk.
To ward against falls in older men, the investigators recommended risk-screening tools used more commonly in noncancer populations. They singled out the Hendrich II Fall Risk Model, which predicts falls based on independent risk factors that include depression, impairments in bladder and bowel function, dizziness, use or cessation of antiepileptic drugs, treatment with benzodiazepines, and poor performance on a “get-up-and-go” test of rising form a seated position. Men who score highly on a screening evaluation will require precautionary interventions. It’s possible that certain bone-health drugs such as denosumab can protect against fracture, but data with these sorts of agents in advanced prostate cancer are limited, so the investigators couldn’t make a strong recommendation either way.
“I welcome this study, since it brings attention to an often overlooked issue in older men, many of whom may be frail and have lost bone density and bone mass as a result of lowered testosterone values resulting from overall treatment,” said Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, editor of the Harvard Health Publishing Annual Report on Prostate Diseases, and editor in chief of HarvardProstateKnowledge.org. “Falls and traumatic fractures are a devastating event for this patient population and studies like this are long overdue. Hopefully with studies like this coming to light, and more data being collected, best practices for fall prevention will be developed and implemented at the point of care.”