Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.
"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."
The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.
In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.
Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.
Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."
There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).
The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).
Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.