Patients with bone metastatic castration-resistant prostate cancer (mCRPC) might benefit from radium-223 (223Ra) combined with
new-generation hormonal agents (NHAs) in terms of survival and quality of life (QoL). However, the safety of combination therapies
remains unclear. Therefore, we aimed to perform a network meta-analysis by reviewing the literature about the combination of
223Ra with abiraterone acetate plus prednisone (AAP) or enzalutamide and to evaluate the safety of combination therapy in bone
mCRPC patients. Ultimately, ten studies (2835 patients) were selected, including four randomized controlled trials (RCTs), five
retrospective cohort studies, and one single-arm study. Overall, there was no difference in the incidence of fracture between the
223Ra+NHA combination group and the 223Ra monotherapy group (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.91–2.34,
P = 0.66), but the incidences in both the 223Ra+NHA combination group (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01) and the 223Ra
monotherapy group (OR: 2.24, 95% CI: 1.23–4.08, P < 0.01) were higher than that in the NHA monotherapy group. However, in
the meta-analysis involving only RCTs, there was no difference between the 223Ra monotherapy group and the NHA monotherapy
group (OR: 1.14, 95% CI: 0.22–5.95, P = 0.88), while the difference between the 223Ra+NHA combination group and the NHA
monotherapy group remained significant (OR: 3.22, 95% CI: 2.24–4.63, P < 0.01). Symptomatic skeletal events (SSEs), SSE-free
survival (SSE-FS), all grades of common adverse events (AEs), and ≥grade 3 AEs among all groups did not show any significant
difference. Our results indicate that the combination of 223Ra with NHAs was well tolerated in bone mCRPC patients compared to 223Ra monotherapy, even though the incidence of fracture was higher in patients who received 223Ra than that among those who
received NHA monotherapy. More evidence is needed to explore the safety and efficiency of 223Ra combination therapies.

Keywords: meta-analysis; metastatic castration-resistant prostate cancer; new-generation hormonal agents; radium-223; safety

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