2nd-generation antiandrogens linked to increased risk of cognitive toxic effects, fatigue, falls

Second-generation antiandrogens (AAs) are associated with an increased risk of cognitive and functional toxic effects, including fatigue and falls, when used as monotherapy or in combination with androgen-deprivation therapy (ADT), results of a systematic review and meta-analysis have shown.

The analysis included 12 randomized controlled trials (n=13,524) of second-generation AAs vs placebo (enzalutamide +/- ADT vs placebo +/- ADT, apalutamide + ADT vs placebo + ADT, abiraterone + prednisone vs placebo + prednisone, or darolutamide + ADT +/- docetaxel vs placebo + ADT +/- docetaxel) in patients with metastatic or nonmetastatic prostate cancer, which reported cognitive toxic effects, asthenic toxic effects, or falls. [JAMA Oncol 2023;doi:10.1001/jamaoncol.2023.0998]

Among four studies (n=5,267) with cognitive toxic effects reported, any-grade cognitive toxic effects occurred in 2–8 percent of patients in the second-generation AA group vs 2–3 percent of those in the control group. The risk of cognitive toxic effects showed a more than two-fold increase with second-generation AAs vs control (risk ratio [RR], 2.10; 95 percent confidence interval [CI], 1.30–3.38; p=0.002), with no evidence of heterogeneity observed (I², 53 percent; 95 percent CI, 0–84 percent; p=0.10). Meta-regression did not support modification of risk of cognitive toxic effects by median age of second-generation AA users (coefficient, -0.07; 95 percent CI, -0.40 to 0.26; p=0.68).

“Results [on risk of cognitive toxic effects] were consistent when examining three studies that included traditional hormone therapy [ie, ADT] in both treatment arms [RR, 1.77; 95 percent CI, 1.12–2.79; p=0.01],” the researchers reported.

Among 12 studies (n=13,524) with fatigue reported, any-grade fatigue occurred in 5–45 percent of patients in the second-generation AA group vs 2–42 percent of those in the control group. The risk of fatigue was increased by 34 percent with second-generation AAs vs control (RR, 1.34; 95 percent CI, 1.16–1.54; p<0.001), with evidence of heterogeneity observed (I², 83 percent; 95 percent CI, 71–90 percent; p<0.001).

“Across studies, greater median age in the intervention group was associated with an increased risk of fatigue with second-generation AAs [coefficient, 0.75; 95 percent CI, 0.04–0.12; p<0.001],” the researchers noted. “[There was also] a higher risk of fatigue among individuals randomized to receive second-generation AAs who had nonmetastatic compared with metastatic disease at enrolment [coefficient, 0.34; 95 percent CI, 0.09–0.58; p=0.007].”

Results on risk of fatigue were consistent when examining five studies that included ADT in both treatment arms (RR, 1.32; 95 percent CI, 1.10–1.58; p=0.003).

The risk of falls showed an 87 percent increase with second-generation AAs vs control (RR, 1.87; 95 percent CI, 1.27–2.75; p=0.001), based on six studies. Furthermore, the risk of grade ≥3 falls was increased by 72 percent with second-generation AAs vs control (RR, 1.72; 95 percent CI, 1.01–2.94; p=0.05). Median age did not modify the risk of falls among recipients of second-generation AAs (coefficient, 0.03; 95 percent CI, -0.18 to 0.24; p=0.80).

“Our findings have practical implications for patient care,” the researchers commented. “As use of second-generation AAs is increasing in prostate cancer, there is an increasing need to identify and treat individuals experiencing adverse cognitive effects.”