The safety of radium-223 combined with new-generation hormonal agents in bone metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis

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