AR Inhibitors Lead to Higher Fall/Fracture Risk in Older Men With Prostate Cancer

December 17, 2020 - Androgen receptor inhibitor–therapy is associated with an increased risk of falls and fractures in patients with prostate cancer. However, since it has shown improvement in overall survival, the benefits may outweigh the risk.

Androgen receptor (AR) inhibitor–therapy is associated with an increased risk of falls and fractures in patients with prostate cancer. However, since it has shown improvement in overall survival (OS), the benefits may outweigh the risk, according to a systematic review and meta-analysis conducted by University of Kentucky researchers.

Investigators determined there were 525 (8%) all-grade falls and 62 (1%) grade 3 or greater falls in patients on AR inhibitors (n = 6536) and 221 (5%) all-grade falls and 28 (0.6%) grade 3 or greater falls in the control group (n = 4846). In the AR-inhibitor group, findings revealed 242 all-grade fractures (4%) compared with 107 all-grade fractures (2%) in the control group. Grade 3 or higher fractures occurred in 60 patients (1%) on AR inhibitors and in 23 (0.5%) in the control group.

AR inhibitors were defined as enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa) alone or in combinations in this systemic review. The investigators included 11 randomized clinical trials (phases 2-4) with 11,382 men who were a median age of 72 years (range, 43-97). They had either nonmetastatic castration-resistant prostate cancer (CRPC), metastatic hormone-sensitive prostate cancer (mHSPC), or metastatic castration-resistant prostate cancer (mCRPC). Most participants were from North America, Europe, Australia, or Canada.

The systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Studies were found using Cochrane, Scopus, and MedlinePlus databases from inception through August 2019.

The patients on AR inhibitors received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations, whereas the control group received placebo, bicalutamide (Casodex), or abiraterone acetate (Zytiga).

Eight studies used enzalutamide, 2 studies used apalutamide, and 1 used darolutamide. The median duration of treatment in the AR-inhibitor group was 15 months (range, 5.4-20.5) vs 8 months (range, 5.4-18.3) in the control group.

Upon examining individual AR inhibitors, results also showed that apalutamide had the highest all-grade fall and fracture rates, at 12% (95% CI, 10.60%-14.21%) and 10% (95% CI, 8.0%-11.3%), respectively. That was followed by enzalutamide (8% fall rates, 1.8% fracture rates) and darolutamide (4.2% for both).

The use of AR inhibitors was associated with an increased risk of all-grade falls (risk ratio [RR], 1.8; 95% CI, 1.42-2.24; P < .001), grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001), all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01), according to the pooled analysis.

“The use of AR inhibitors is associated with 1.8 times higher risk of fall and 1.6 times higher risk of fracture,” lead study author Zin W. Myint, MD, and coinvestigators wrote. “[However], AR [inhibitors] are novel hormonal agents with substantial OS improvement in patients with [nonmetastatic] CRPC, mHSPC, and mCRPC.”

Although investigators don’t fully understand why AR inhibitors are associated with higher fall and fracture risk, they laid out several possible reasons. First, this class of drugs can cross the blood–brain barrier. Other possible reasons include sarcopenia, which is associated with AR inhibitors; concomitant medications, such as benzodiazepines or opioid medications; fatigue from disease and/or as an adverse effect of ARIs; underlying predisposing conditions, such as cognitive impairment, depression, or multiple medical comorbidities; poor performance status; and history of falls.

Limitations to the study include the degree of fall and fracture, severity of fall and fracture, and the clinical consequences of fall and/or fracture on therapy. In addition, the use of bone-health agents was not reported in the primary studies. “Oncologists should consider incorporating the fall-risk screening tool in older, active, patients with cancer in clinics,” the authors wrote. “Appropriate use of bone-targeted agents should be considered in those patients as per established guidelines.”

Because most of the studies included in the meta-analysis were enzalutamide-based, investigators expressed that an update is warranted when more prospective trials are published with apalutamide and darolutamide.

Investigators concluded that although the incidence of falls and fractures were a higher risk in patients receiving AR inhibitors, it is still a rare adverse event, and therefore risk should be evaluated for each individual and considered in cancer care.


Myint ZW, Momo HD, Otto DE, et al. Evaluation of fall and fracture risk among men with prostate cancer treated with androgen receptor inhibitors: a systematic review and meta-analysis. AMA Netw Open. 2020;3(11):e2025826. doi:10.1001/jamanetworkopen.2020.25826