Second-generation antiandrogens (AAs) ― abiraterone, apalutamide, darolutamide, and enzalutamide ― are a cornerstone of modern prostate cancer treatment, improving outcomes and survival.
However, they carry a significant caveat, according to a new meta-analysis of 12 clinical trials with over 13,000 patients.
These drugs come with a substantial risk of cognitive problems and fatigue and increase the risk of falls by 87%, the authors report.
These findings carry “important public health indications” because use of second-generation AAs, currently first-line treatment for advanced and castration-resistant prostate cancer, is expanding with new indications, meaning that the pool of men at risk for such problems is large and growing, the team comments.
The take-home message is that the findings give men ― and the physicians who counsel them ― a fuller idea of what to expect when considering using the agents, the researchers comment. This information is key at a time when so much of prostate cancer treatment involves carefully weighing the risks and benefits, they add.
The study was published May 25 in JAMA Oncology. It was conducted by a team of researchers from MD Anderson Cancer Center, Houston, Texas, and was led by Malgorzata Nowakowska, a medical student at Baylor College of Medicine in Houston.
Two prostate cancer specialists agreed and gave an example to bring the point home in an accompanying editorial.
The risk-benefit ratio of adding a second-generation AA to treatment may be different for a patient who wants to stay alert and sharp to keep a complex job “versus someone whose primary goal is to see their young children graduate high school,” Alexandra Sokolova, MD, of the Oregon Health and Science University, Portland, and Julie Graff, MD, of the VA Portland Health Care System, write in their editorial.
The study fills a “critical gap” when it comes to counseling men about the drugs and will help guide discussions, they say.
The investigators say their study also highlights the need for additional research to identify who is most at risk for the side effects and the best way to prevent and treat them. “Interventions currently under investigation include donepezil, methylphenidate, low-fat diet, acupuncture, martial arts, and high-intensity exercise, among many others,” Nowakowska and her colleagues note.
The 12 trials in the meta-analysis, which compared second-generation AAs to placebo, were conducted from 2008 to 2021. These trials were multinational investigations that included patients with metastatic disease as well as those with nonmetastatic disease. The median age across the studies ranged from 67 to 74 years, and trial follow-up ranged from 3.9 to 48 months.
The rates of adverse cognitive effects and attention disorders and disturbances ranged from 2% to 8% among patients who received second-generation AAs, vs 2% to 3% among those who received placebo, a more than doubling of the risk of cognitive toxic effects (P = .002).
Fatigue of any grade was reported in 5% to 45% of participants taking second-generation AAs, vs 2% to 42% of patients taking placebos, which translates to a 34% higher risk (P < .001).
The use of AAs was associated with an 87% increase in the risk of falls in comparison with placebo, regardless of severity. For falls of grade 3 or higher that required hospitalization or invasive treatment, the increase in risk with second-generation AAs was 72% (P = .05).
The findings were consistent for cognitive toxicity and fatigue in studies that included traditional hormone therapy in both the treatment and control arms. Increased age was associated with a greater risk of fatigue.
Study limits include the fact that it was not known how long patients were taking the drugs before they encountered problems. In addition, the findings were not broken down with respect to medication, so it’s unknown whether such problems are worse with some second-generation AAs than with others.
The editorialists note that real-world patients tend to be older and sicker than patients in trials, so the risk of falls, fatigue, and cognition problems might be higher among everyday patients.
The study was funded by the National Institutes of Health and others. The investigators have disclosed no relevant financial relationships. Sokolova has received personal fees from Lantheus and travel grants from AstraZeneca. Graff has received nonfinancial support from Janssen, Pfizer/Astellas, and Sanofi.
JAMA Oncol. Published online May 25, 2023. Abstract, Editorial
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]
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