Radium-223: a winning duo with enzalutamide?

By Ana Espino | Published on November 25, 2025 | 2 min read


Metastatic castration-resistant prostate cancer (mCRPC) represents an advanced and aggressive stage of the disease in which tumor cells continue to progress despite androgen suppression. It is characterized in most cases by bone metastases, which are responsible for considerable morbidity and increased mortality. These bone lesions expose patients to debilitating pain, pathological fractures, and serious complications such as spinal cord compression.  

Despite advances brought by next-generation hormonal therapies such as enzalutamide and the introduction of targeted chemotherapies, therapeutic options remain limited for achieving durable control of bone progression. Radium-223, an alpha-emitting radioisotope that specifically targets bone metastases, demonstrated a survival benefit in the ALSYMPCA trial. However, its use has been restricted due to an increased risk of fractures, particularly when combined with other treatments without bone protection. This highlights one of the major current challenges: offering treatment combinations that are both effective and safe in terms of bone toxicity.  

It is within this context that the PEACE-3 study was initiated, aiming to assess whether adding radium-223 to enzalutamide could improve radiographic progression-free survival in patients with mCRPC and bone metastases.  

Combining to improve control?  

In this study, 446 patients with mCRPC and bone metastases were included. They were randomly assigned to one of the following arms:  

• Enzalutamide alone
• Enzalutamide plus radium-223

 
All patients received bone-protective treatment, either zoledronic acid or denosumab. The primary endpoint was radiographic progression-free survival. Secondary endpoints included overall survival, time to next treatment, pain progression, and the occurrence of symptomatic skeletal events.  

The results show a significant benefit of the combination on radiographic progression-free survival. An interim analysis of overall survival also suggests a benefit, with a median of 35 months in the control arm versus 42.3 months in the experimental arm. Time to next treatment was significantly prolonged in the combination arm.  

However, the combination did not show a demonstrated benefit regarding pain progression or reduction of symptomatic skeletal events. Concerning tolerability, the frequency of grade ≥3 adverse events was higher in the combination arm (65.6% vs. 55.8%), notably due to an increased incidence of bone fractures. Nevertheless, the mandatory implementation of bone-protective therapy helped reduce this risk during the second phase of the study.  

A new ally in the anti-mCRPC arsenal?  

Castration-resistant prostate cancer with bone involvement remains a condition with major clinical impact, for which current treatments struggle to provide durable control without excessive toxicity. The objective of PEACE-3 was to explore the added value of radium-223 combined with enzalutamide, while minimizing bone risks. The results confirm the effectiveness of this combination in terms of progression-free survival and suggest improved overall survival, without compromising tolerability when bone prophylaxis is implemented.  

However, the study has certain limitations. Overall survival follow-up remains incomplete, as the study is still in the interim analysis phase. Its open-label design may introduce biases, notably in the selection of subsequent treatments. Finally, the results cannot be extrapolated to patients with visceral metastases, who were excluded from the study.  

Nevertheless, these findings open clear perspectives. The enzalutamide–radium-223 combination, with bone prophylaxis, could be incorporated as a first-line therapy for patients with bone-predominant mCRPC. Future studies could also explore sequential or triple-agent combinations and assess their benefit in patients with low tumor burden or oligometastatic disease.

Read next: Treatment of prostate cancer with GnRH agonists: what is the real impact on quality of life?