Radium-223 Poised to Move Beyond Prostate Cancer

The alpha particle–emitting radiopharmaceutical radium-223 (Xofigo) is set to expand beyond prostate cancer, given the agent's potent efficacy and mild toxicity profile for patients with osteoblastic metastases.

Brian Lewis, MD

The alpha particle—emitting radiopharmaceutical radium-223 (Xofigo) is set to expand beyond prostate cancer, given the agent’s potent efficacy and mild toxicity profile for patients with osteoblastic metastases, according to a review article published in the journal Oncology.1

At this time, radium-223 is the first and only FDA-approved alpha—emitting radiopharmaceutical. The agent was approved in May 2013 for men with symptomatic metastatic castration-resistant prostate cancer (mCRPC) that had spread to the bones but not other organs, based on findings from the phase III ALSYMPCA trial. In this trial, median overall survival was 14.9 months with radium-223 and 11.3 months with placebo (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83; P <.001).2

“Currently, alpha particle therapy is limited to one agent and one disease,” wrote Brian Lewis, MD, and colleagues. “Given the potent and desirable properties of alpha particles with regard to the induction of DNA strand breaks, one can readily envision targeted alphas being used in many diseases.”

Clinical trials are currently assessing radium-223 across a variety of osteoblastic bone-forming tumors. Two separate phase II studies are comparing the radiopharmaceutical with placebo in patients with bone predominant HER2-negative, hormone receptor¬—positive metastatic breast cancer. In one of the studies, patients in both arms will receive a backbone of hormonal therapy (NCT02258464); in the other, everolimus (Afinitor) and exemestane will be administered. Assessment of symptomatic skeletal event-free survival is the primary endpoint for both studies.

In addition to breast cancer, a phase II study is assessing radium-223 in patients with radioactive iodine-refractory bone-metastatic differentiated thyroid cancer. The primary endpoint of this investigation is metabolic response, per PERCIST criteria (NCT02390934). Additionally, a phase I study is assessing radium-223 with VEGF-targeted therapy in patients with bone-metastatic renal cell carcinoma. The primary endpoints of this study are biomarkers of osteoblast and osteoclast activity (NCT02406521).

“Many patients beside prostate cancer patients have bone metastases, and the mechanism of action of radium-223 is such that almost any osteoblastic bone-forming tumor would potentially be susceptible to treatment with this agent,” the authors explained. “Trials in other tumors are being conducted, and overviews on this topic have been published.”

As a calcium mimic, radium-223 is effective in patients with osteoblastic metastases. Additionally, other biomarkers are emerging, as interest into the agent expands into other types of cancer. At this time, serum bone alkaline phosphatase (ALP) levels are emerging as a leading indicator of response.

In the ALSYMPCA trial, ALP levels were normalized in 34% of patients receiving radium-223 compared with just 1% for those treated with placebo. Additionally, time to increase in ALP was significantly longer with radium-223 versus placebo (7.4 vs 3.8 months; HR, 0.17; P < .001).

“It is clear that alkaline phosphatase serves as a pharmacodynamic biomarker for radium-223 in patients with prostate cancer metastatic to bone,” the authors of the review noted. “Multiple myeloma is an osteolytic tumor when it affects the bone, and most would consider it to be a poor radium-223 target; interestingly, however, after successful treatment with agents such as bortezomib, the bone healing that occurs is associated with increased bone formation, a rise in alkaline phosphatase levels, and increased radium-223 uptake on bone scans.”

In the past 5 years, multiple therapies have gained approval for men with CRPC. Given the efficacy in prostate cancer, clinical trials continue to assess radium-223 in conjunction with other effective therapies.

Clinical trials are currently exploring combination strategies for patients with mCRPC, including a three-arm phase IIa investigation assessing abiraterone acetate (Zytiga) or enzalutamide (Xtandi) with radium-223 or radium-223 alone (NCT02034552). Additionally, a phase III study is looking at abiraterone plus radium-223 in men with bone-metastatic CRPC prior to the administration of chemotherapy (NCT02043678). A similar phase III study is expected to begin enrolling soon to test enzalutamide plus radium-223 (NCT02194842).


  1. Lewis B, Chalhoub E, Chalouhy C, et al. Radium-223 in bone-metastatic prostate cancer: current data and future prospects. Oncology. 2015;29(7):483-488.
  2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.