Meta-analysis links ARPI-containing prostate cancer therapies with higher reported fracture adverse-event risk

A systematic review and meta-analysis found that androgen receptor pathway inhibitor-containing therapies were associated with higher cumulative risks of trial-reported fracture-related adverse events among men with prostate cancer than randomized control treatments. The abstract reports relative risks of 2.13 for all-grade fracture-related adverse events and 2.64 for events of grade 3 or higher, based on pooled results from eligible phase III randomized trials.

Researchers searched PubMed/MEDLINE, the Web of Science Core Collection and Cochrane CENTRAL from database inception through 20 August 2026. The review included phase III randomized trials evaluating abiraterone, enzalutamide, apalutamide or darolutamide, regardless of whether the studies reported fracture outcomes. Twenty-two trials met the eligibility criteria. Thirteen trials, involving 13,712 participants, contributed data for all-grade fracture-related adverse events, while eight trials, involving 9,254 participants, contributed data for grade 3 or higher events.

Risk ratios were pooled with random-effects models using restricted maximum-likelihood estimation and a Hartung–Knapp adjustment. For all-grade fracture-related adverse events, the pooled risk ratio was 2.13 (95% confidence interval, 1.74–2.60), with statistical heterogeneity of 45.8% and a 95% prediction interval of 1.23–3.68. For grade 3 or higher events, the pooled risk ratio was 2.64 (95% confidence interval, 1.73–4.02), with heterogeneity of 11.8%. The corresponding pooled cumulative risk differences were 4.93 percentage points for all-grade events and 1.71 percentage points for grade 3 or higher events, although the abstract cautions that these estimates require caution because observation periods and baseline fracture risks differed among trials.

Exploratory analyses suggested possible differences among the four agents, but no interaction was observed by prostate cancer disease state. These subgroup findings were based on indirect comparisons and were imprecise in several groups. The direction of the associations remained statistically stable in sensitivity and rare-event analyses, but differences in fracture definitions and treatment exposure across trials remained unresolved. The findings therefore describe associations with adverse events as reported in randomized trials, rather than establishing a uniform fracture risk for every individual receiving an ARPI-containing regimen.

Subject of Research: Reported fracture adverse-event risks with androgen receptor pathway inhibitor-containing therapies for prostate cancer

Article Title: Evaluation of bone fracture risk among men with prostate cancer treated with androgen receptor pathway inhibitor-containing therapies: a systematic review and meta-analysis

Article References: Zhu, J., Zhang, A., Jing, W., & Zhang, F. (2026). Evaluation of bone fracture risk among men with prostate cancer treated with androgen receptor pathway inhibitor-containing therapies: a systematic review and meta-analysis. BMC Cancer. https://doi.org/10.1186/s12885-026-16982-4

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16982-4

Keywords: prostate cancer, androgen receptor pathway inhibitors, fracture risk, adverse events, systematic review, meta-analysis, randomized trials, abiraterone, enzalutamide, apalutamide, darolutamide, Evaluation