Second-generation anti-androgens (AAs) for the treatment of prostate cancer are associated with an increased risk of cognitive and functional toxic effects, according to results from a systematic review and meta-analysis.
Across 12 randomized trials involving over 13,000 patients, increased risks of cognitive toxic effects (risk ratio [RR] 2.10, 95% CI 1.30-3.38, P=0.002) and fatigue (RR 1.34, 95% CI 1.16-1.54, P<0.001) were observed in patients treated with second-generation AAs compared with those in control arms, reported Kevin T. Nead, MD, MPhil, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues.
The findings were consistent when the analysis was limited to studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR 1.77, 95% CI 1.12-2.79, P=0.01) and fatigue (RR 1.32, 95% CI 1.10-1.58, P=0.003), they noted in JAMA Oncology.
They also found that a greater median age was associated with a greater risk of fatigue with second-generation AAs (coefficient 0.75, 95% CI 0.04-0.12, P<0.001).
In addition, the use of AAs was associated with increased falls (RR 1.87, 95% CI 1.27-2.75, P=0.001). The observed increased risk of falls — which included those that required hospitalizations and invasive interventions — “indicates the importance of counseling patients on fall risk and implementing preventive measures as appropriate,” Nead and team said.
“To our knowledge, these results are the first to suggest an association between second-generation AAs and cognitive and functional toxic effects based on data from prospective RCTs [randomized clinical trials],” the authors wrote. “Our work supports the need for further research to determine how to identify, prevent, and treat cognitive and functional toxic effects in patients treated with second-generation AAs.”
Nead and team said their findings have important implications for patient care.
“Because use of second-generation AAs is becoming more prevalent in prostate cancer treatment, there is an increasing need to identify and treat individuals experiencing adverse cognitive effects,” they noted, adding that timely interventions for these patients should be feasible since they have regular healthcare exposures.
In a commentary accompanying the study, Alexandra O. Sokolova, MD, and Julie N. Graff, MD, both of the Knight Cancer Institute at Oregon Health & Science University in Portland, agreed that the results suggest clinicians should carefully consider the risks and benefits when prescribing these therapies for individual patients.
“Ultimately, the goal of prostate cancer treatment is to improve patients’ quality of life while minimizing the risk of adverse outcomes, and this study provides valuable information to help achieve that goal,” they wrote.
Currently, there are four second-generation AAs approved by the FDA for metastatic hormone-sensitive prostate cancer: abiraterone (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa). While these agents have improved patient survival, Nead and colleagues noted that retrospective evidence suggests there is an association between these drugs and adverse cognitive and functional outcomes. However, they added, “further data from prospective trials are needed.”
Their systematic review and meta-analysis included 12 studies comprising 13,524 patients, all of which were multinational with data collection that occurred between 2008 and 2021.
All participants had metastatic and nonmetastatic prostate cancer at enrollment, with a median age across studies of 67 to 74 in both the intervention and control arms. Study follow-up time ranged from 3.9 to 48 months.
Nead and colleagues acknowledged several limitations to their study. For example, they used tabular summary count data that didn’t account for time to event. Therefore, they reasoned that if second-generation AAs resulted in increased survival, that could bias the results since patients treated with AAs are more likely to be alive and experience toxic effects.
“Regardless, the large magnitude of increased risk combined with the large absolute number of toxic effects reported suggest that these toxic effects are important to consider when counseling and managing treatment in this group of patients,” they wrote.
This research was supported by a grant from the NIH.
Nead was supported by grants from the National Cancer Institute. A co-author was supported by grants from the Cancer Prevention and Research Institute of Texas and the National Cancer Institute.
The study authors had no other disclosures.
Sokolova reported personal fees from Lantheus and travel grants from AstraZeneca.
Graff reported nonfinancial support from Janssen, Pfizer/Astellas, and Sanofi.
Source Reference: Nowakowska MK, et al “Association of second-generation antiandrogens with cognitive and functional toxic effects in randomized clinical trials: a systematic review and meta-analysis” JAMA Oncol 2023; DOI: 10.1001/jamaoncol.2023.0998.
Source Reference: Sokolova AO, Graff JN “Balancing treatment benefits of androgen-receptor signal inhibitors and quality of life in patients with prostate cancer” JAMA Oncol 2023; DOI: 10.1001/jamaoncol.2023.0982.