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

Abstract

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.

Safety and effectiveness of the radium‐223–taxane treatment sequence in patients with metastatic castration‐resistant prostate cancer in a global observational study (REASSURE)

“…22,23 However, other studies and meta-analyses indicate that the combination of radium-223 and AR-targeted therapy is effective, and the risk of fracture can be reduced by concomitant use of BHAs such as denosumab or zoledronic acid. [24][25][26][27][28][29][30][31] The ongoing…”

“…The ERA‐223 study indicated increased risk of fracture when abiraterone acetate and radium‐223 were used together versus abiraterone alone, 21 resulting in regulatory restrictions on this combination 22,23 . However, other studies and meta‐analyses indicate that the combination of radium‐223 and AR‐targeted therapy is effective, and the risk of fracture can be reduced by concomitant use of BHAs such as denosumab or zoledronic acid 24–31 . The ongoing phase 3 PEACE III study (NCT02194842) will assess the efficacy and safety of radium‐223 combined with enzalutamide.…”