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Higher Risk of Falls/Fractures With Androgen Receptor Inhibitors

An increase in the risk of falling and fracturing bones was associated with the use of androgen receptor inhibitors (ARIs) for the treatment of prostate cancer, a systematic review and meta-analysis suggests.

“We know from this meta-analysis that the use of ARIs is associated with a 1.8 times higher risk of falls and a 1.6 times higher risk of fracture,” lead author Zin Myint, MD, Markey Cancer Center, University of Kentucky, Lexington, told Medscape Medical News in an email.

“However, these are still rare side effects, and we also know from phase 3 studies that the ARIs significantly prolong overall survival, so the benefits of ARIs [still] outweigh the risks of falls and fractures,” he added.

In the review, ARI use included enzalutamide (Xtandi), apalutamide (Erleada), or darolutamide (Nubeqa) alone or in combination with androgen deprivation therapy (ADT), but did not include abiraterone (Zytiga) or bicalutamide (Casodex).

The meta-analysis was published online November 17 in JAMA Network Open.

The findings suggest treatment with ARIs is associated with greater risk of falls in men with prostate cancer, said Carol Stone, MD, consultant in palliative medicine, Belfast Health and Social Care Trust and Marie Curie Hospice, Northern Ireland, UK, who was asked for comment.

“However, the frequency of falls in both active and control arms is likely to be an underestimation related to the exclusion of patients with cardiovascular comorbidities, selection bias affecting entry into the original studies, and recall bias that affects accurate reporting of falls,” she said in an email.

Nevertheless, Stone did agree with the authors that all patients with prostate cancer should be screened to assess their risk of falls at each oncology outpatient review.

“Those identified to be at risk [for falls] should have a multifactorial risk assessment and targeting of identified modifiable risk factors,” she said.  

ARI Treatment vs Controls

The review included 11 studies involving a total of 11,382 men with prostate cancer. Diagnoses included nonmetastatic castration-resistant prostate cancer, metastatic hormone-sensitive prostate cancer, or metastatic castration-resistant prostate cancer. The median age of patients was 72 years.

Patients were categorized into those who had been treated with an ARI (n = 6536), either alone or in combination with ADT, and those who had not (n = 4846). The control patients had received placebo, ADT, bicalutamide, abiraterone, or a combination that did not include an ARI.

Patients were excluded from the 11 studies if they had comorbidities including myocardial infarction, congestive heart failure, ventricular arrhythmia, unstable angina, heart block, bradycardia, uncontrolled hypertension, and seizure disorders.

The use of ARIs was associated with a 1.8 times higher risk of all-grade falls and a 1.6 higher risk of grade ≥ 3 falls compared with controls (both P < .001), Myint and colleagues report.

Similarly, the risk of all-grade fractures was almost 1.6 times higher in the ARI group compared with controls (P < .001), and the risk of grade ≥ 3 fractures was 1.7 times higher than controls (P = .01).

Grade ≥ 3 falls and fractures meant that the fall or fracture was severe enough to require hospital admission for care, and patients with lower grade falls and fractures were treated as outpatients.

Table 1. Falls and Fractures in the ARI and Control Groups

Outcome ARI group, % Control group, %
All-grade falls 8 5
Grade ≥ 3 falls 1 0.6
All-grade fractures 4 2
Grade ≥ 3 fractures 1 0.5

 

In terms of the reported incidence of all-grade falls associated with individual ARIs, apalutamide had the highest rate at 12%, followed by enzalutamide at 8% and darolutamide at 4.2%, Myint and colleagues observe.

“Similarly, apalutamide was associated with the highest all-grade fractures rate at 10%…followed by enzalutamide at 1.8%…and darolutamide at 4.2%,” the authors report.

Mechanism of Action

All three drugs — apalutamide, enzalutamide, and darolutamide — are nonsteroidal androgen receptor antagonists.

Enzalutamide and apalutamide share a similar molecular structure with a high affinity for the ligand-binding domain of the androgen receptor. In contrast, darolutamide has a unique molecular structure with an active metabolite that inhibits testosterone-induced downstream effects of DNA activation, prostate cancer cell growth, and survival.

“To date, it is unclear why the ARI drug class is associated with a higher risk of falls,”  the researchers acknowledge.

One possibility is that enzalutamide and apalutamide can cross the blood–brain barrier, and can therefore be used to treat brain metastasis.

Darolutamide does not appear to cross the blood–brain barrier, and thus, has fewer central nervous system adverse effects, including falls, than the other two agents.

“Another possible explanation is that sarcopenia associated with ARIs has a higher risk for fall,” investigators suggest.

It has been shown that enzalutamide used alone was associated with a significant decrease in mean body mass, and that used together with ADT, the doublet may be associated with a higher risk of muscle loss and sarcopenia, the researchers note.

Another possibility is that other drugs, such as benzodiazepines or opioid medication, used to treat concomitant symptoms, fatigue from the disease or treatment, poor performance status, and even a history of falls could increase the risk of falls and fractures.

As the authors note, there are several fall risk-assessment tools for noncancer patients, including the Hendrich II Fall Risk Model and 12-item Fall Risk Questionnaire. They suggest that “physicians should incorporate this fall risk model in clinical practice, especially in patients taking high-risk medications or patients with pre-existing conditions who have a high risk of fall.”

“Appropriate use of bone-targeted agents should be considered in those patients as per established guidelines,” they add.

Myint and all coauthors except one have reported no relevant financial relationships; Kolesar has reported receiving ownership interest from Helix Diagnostics outside the submitted work. Stone has reported no relevant financial relationships.

JAMA Netw Open. Published online November 17, 2020. Full text

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