Trial-reported arthralgia of androgen deprivation therapy plus androgen receptor signaling inhibitors in prostate cancer: evidence from phase III randomized trials

Androgen receptor signaling inhibitors (ARSIs) are widely used in prostate cancer. However, their association with arthralgia remains incompletely explored. This systematic review and meta-analysis evaluated the risk of all-grade and grade ≥ 3 arthralgia in patients with prostate cancer related to ARSIs. PubMed, Web of Science, the Cochrane Library, and ClinicalTrials.gov were searched to identify phase III randomized controlled trials comparing ARSI-based treatment with placebo or standard care without a second-generation ARSI. The primary outcomes were risk ratios (RRs) for all-grade and grade ≥ 3 arthralgia. Pooled estimates were calculated using a random-effects model with restricted maximum likelihood estimation and Hartung-Knapp adjustment. Subgroup analyses were performed according to individual ARSI agent and disease setting. A total of 13 phase III randomized controlled trials involving 11,751 patients were included. ARSI treatment was associated with a significantly increased risk of all-grade arthralgia compared with control treatment (RR 1.26, 95% CI 1.06–1.48), with moderate heterogeneity. In drug-specific subgroup analyses, increased all-grade arthralgia risk was observed with abiraterone (RR 1.21, 95% CI 1.12–1.31), enzalutamide (RR 1.31, 95% CI 1.00–1.72), and apalutamide (RR 2.42, 95% CI 1.70–3.45), whereas darolutamide was not associated with an increased risk (RR 1.00, 95% CI 0.81–1.22). For grade ≥ 3 arthralgia, ARSI treatment was not associated with a significant increase in risk (RR 1.13, 95% CI 0.68–1.90). In conclusion, ARSI therapy was associated with an increased risk of all-grade arthralgia but not grade ≥ 3 arthralgia. These findings may inform pre-treatment counseling and early monitoring of arthralgia during ARSI therapy, although the analysis of grade ≥ 3 arthralgia should be interpreted cautiously because severe events were rare.