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 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 (223)Ra 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 (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)Ra 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 (223)Ra monotherapy group and the NHA monotherapy group (OR: 1.14, 95% CI: 0.22–5.95, P = 0.88), while the difference between the (223)Ra+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 (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 who received NHA monotherapy. More evidence is needed to explore the safety and efficiency of (223)Ra combination therapies.