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BOSTON -- Men with metastatic castration-resistant prostate cancer (CRPC) lived significantly longer when treated with a bone-targeted, alpha-emitting agent, a randomized trial showed.

Median overall survival increased by 3.6 months in men who received radium-223 (Alpharadin) compared with placebo. The time to a first skeletal-related event (SRE) increased significantly, and the radium-223 group had a significant delay in the time to first application of radiation to bone, as reported here at the American Society for Radiation Oncology.

"Radium-223 was very well tolerated and associated with a highly favorable safety profile," said Howard Sandler, MD, of Cedars-Sinai Medical Center in Los Angeles. "Radium-223 is a first-in-class alpha-emitter that may provide a new standard of care for the treatment of castration-resistant prostate cancer patients with bone metastases."

More than 90% of men with metastatic CRPC have radiologic evidence of bone metastases, which cause substantial disability, adversely affect quality of life, increase treatment cost, and contribute to disease-related mortality. Much of the disability and adverse impact on quality of life result from SREs, including spinal cord compression, pathologic fracture, and need for surgery or external-beam radiation therapy.

A therapy that would reduce the adverse bone effects of CRPC would have a favorable impact on multiple physiologic and psychosocial outcomes in patients with CRPC, Sandler noted. Radium-223 has demonstrated potential to fill that therapeutic void.

The alpha-emitting agent acts as a calcium mimetic and naturally and specifically targets new bone growth in and around bone metastases. Alpha particles induce double-strand DNA breaks in tumor cells, and brief penetration causes localized tumor-cell killing with minimal change to surrounding normal tissue, Sandler continued.

As previously reported, initial results of a randomized, placebo-controlled clinical trial showed a 3-month improvement in median overall survival with radium-223 versus placebo. The benefit was based on findings from a planned interim analysis, which led to discontinuation of the trial.

Sandler reported final results with complete follow-up in all patients. The study involved 921 patients with symptomatic CRPC, at least two bone metastases, no visceral metastases, and progression on docetaxel or not a candidate for docetaxel.

Patients were randomized 2:1 to radium-223 or placebo, each added to best supportive care. The primary endpoint was overall survival. Principal secondary endpoints included multiple bone-specific outcomes.

Baseline characteristics showed that 85% to 86% of the patients had ECOG performance status 0 or 1, 40% had more than 20 metastases, and an additional 44% to 48% had six to 20 metastases. About half the patients had received external beam radiation therapy (EBRT) to bone.

At the interim analysis, the radium-223 arm had a median overall survival of 14.0 months compared with 11.2 months in the placebo group. The difference represented a 30% reduction in the hazard ratio in favor of radium-223 (P=0.0019).

The final analysis showed a median overall survival of 14.9 months in the radium-223 group versus 11.3 months in the placebo group. The reduction in the hazard ratio remained 30%, but the statistical significance had increased (P=0.0001).

Subgroup analysis showed a consistent benefit in favor of radium-223, irrespective of alkaline phosphatase level, bisphosphonate use, history of exposure to docetaxel, and baseline performance status.

Radium-223 was associated with a significant delay in the time to a first SRE, a median of 13.5 months versus 8.4 months with placebo, representing a 39% reduction in the hazard ratio (P=0.0005). As with the primary endpoint, the SRE benefit was consistent across prespecified subgroups.

Treatment with radium-223 also delayed the time to first use of EBRT (17.0 versus 10.9 months, HR 0.65, P=0.0038).

Analysis of individual types of SREs showed significant advantages for radium-223 with respect to use of EBRT (23% versus 27%, P=0.0038), spinal cord compression (3% versus 6%, P=0.016), and pathologic fracture (4% versus 7%, P=0.013).

Radium-223 added minimal toxicity, as hematologic and nonhematologic toxicity was similar to or lower than that observed in the placebo group.

Invited discussant Jason Efstathiou, MD, PhD, seconded Sandler's suggestion that the results make a case for radium-223 as a new standard of care for metastatic CRPC, pending FDA approval of the agent. The positive results also make a case for a forward-looking attitude toward the agent.

"Use of radium-223 in earlier disease-state settings and in combination with other agents or treatments requires further study," said Efstathiou, of Harvard Medical School.

"It remains to be seen whether there will be a broad use of a radiopharmaceutical. Radiation oncologists need to know about it and should feel free to prescribe it."

Sandler noted that an expanded-access program for radium-223 has already begun in the U.S. and Europe. A phase I/II trial in combination with docetaxel patients with CRPC and bone metastases has already begun. The agent also is being investigated in breast cancer patients with bone-dominant disease and who are considered unsuitable for hormonal therapy.

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