February 1, 2012 — The investigational radiopharmaceutical radium-223 chloride (Alpharadin, Bayer) "may provide a new standard of care" for patients with castration-resistant prostate cancer (CRPC) and bone metastases, say researchers, who reported details from a pivotal trial of the product at the 2012 Genitourinary Cancers Symposium (GUCS), being held in San Francisco, California.
The trial, known as ALSYMPCA (NCT00699751), was stopped early last year when an interim analysis found a significant improvement in survival; patients in the radium-223 group had a longer median survival than those in the placebo group (14.0 vs 11.2 months; hazard ratio [HR], 0.699; P = .0022).
This study was originally presented at the 2011 European Multidisciplinary Cancer Congress, as reported by Medscape Medical News. At the time, principal investigator Chris Parker, MD, consultant clinical oncologist at the Royal Marsden Hospital, London, United Kingdom, said the product represents a "very different and significant step forward" in the treatment of advanced prostate cancer. Other experts agreed: Jean-Charles Soria, MD, PhD, from the Institut Gustave Roussy, Paris, France, predicted that this product will become a "major player in prostate cancer management"; Michael Baumann, MD, professor of radiation oncology at the University of Technology in Dresden, Germany, described the findings as "practice changing."
More results, including data from secondary end points, will be presented at GUCS. They were discussed by one of the study authors, Oliver Sartor, MD, medical director of the Tulane Cancer Center in New Orleans, Louisiana, at a presscast organized by the American Society of Clinical Oncology, one of the sponsors of the meeting.
The novel alpha-emitting radium-223 chloride, originally developed by the Norwegian company Algeta ASA, is now under development by Bayer.
Bayer said recently that it intends to file the results of this prostate cancer trial with regulatory authorities in the United States and Europe in mid-2012, and noted that the product has already been granted a fast-track designation by the US Food and Drug Administration (FDA) for this indication.
American prostate cancer experts taking part in the presscast said they hoped to be using the drug in their patients before the end of the year.
Very Local Action
Radium-223 chloride homes in on bone metastases, Dr. Sartor explained. The bone surrounding a metastasis becomes altered and the bone stroma contains a lot of calcium, he said. The product mimics the calcium and is taken up and deposited in this altered matrix; it then emits alpha particles, but very locally.
These alpha particles have very short penetration; they travel across only about 2 to 10 cell diameters, he noted. Although "they are like little bombs going off," this effect is contained, so does not damage any of the surrounding tissue, he explained.
The ALSYMPCA trial was conducted in 922 patients with CRPC and 2 or more bone metastases (but no visceral metastasis). Although the majority had progressed on docetaxel, some patients considered unfit for docetaxel were included in the trial, Dr. Sartor reported.
Patients were randomized in a 2:1 ratio to receive intravenous radium-223 (50 kBq/kg) or placebo. Patients in both groups also received the best standard of care, which could include further hormonal manipulation and radiation, Dr. Sartor noted.
In addition to a significant improvement in overall survival — which led to the trial being halted early — there was a significant improvement in the time to a skeletal-related event (median, 13.6 vs 8.4 months; HR, 0.610; P = .00046).
In addition, 3 of 4 skeletal-related event components were significantly improved, Dr. Sartor reported. Two of these measures were halved by radium-223 — pathologic bone fractures (3.6% vs 6.7%; HR, 0.45; P =. 013) and spinal cord compression (3.1% vs 6.0%; HR, 0.44; P = .016). The improvement in spinal cord compression is "very clinically significant" because it can lead to great discomfort, he added.
In addition, significantly fewer patients in the radium-223 group than in the placebo group received external-beam radiation (22.6% vs 26.9%; HR, 0.65; P = .0038).
Only 1 of the 4 measures — surgical intervention — was not significantly altered by radium-223 (1.7% vs 1.9%; HR, 0.80; P = .69).
The product is "extremely well tolerated," Dr. Sartor noted. The data he presented showed a very slight increase over placebo for most of the adverse effects, with the exception of bone pain, which was reduced.
Grade 3/4 Adverse Events Reported in ALSYMPCA
|Events||Radium-223 Chloride, %||Placebo, %|
Dr. Sartor noted that the data from this trial should be sufficient for the approval of radium-223 chloride, and said that it might offer a "new standard of care for patients with CRPC and bone metastases."
One of Several New Agents
At the same presscast, data were presented on the use of the investigation drug MDV3100 (Medivation) in a similar patient population of CRPC patients who had progressed on docetaxel. They also showed a significant improvement in survival. Although these 2 drugs are mechanistically very different, they were both well tolerated in a sick population, so there is hope that in the future they could be used in combination, said presscast moderator Nicholas Vogelzang, MD, from US Oncology Research.
The question of which drug to use when will be intensified when these 2 drugs are approved; they will be joining 3 drugs recently approved for use in a similar population of patients with advanced prostate cancer patients — abiraterone (Zytiga, Cougar Biotechnology), carbazitaxel (Jevtana, sanofi-aventis), and the vaccine sipuleucel-T (Provenge, Dendreon).
It was only in 2009 that there was just 1 drug showing a survival advantage in the CRPC setting — docetaxel; now there are quite a few, Dr. Vogelzang said.
Each drug on its own has been shown to improve survival, but it is likely that combinations of these drugs, or using them in sequence, "may add even more value. While we have an important step forward now, it may be even more important in the future," Dr. Sartor said.
2012 Genitourinary Cancers Symposium (GUCS): Abstract 8. To be presented February 2, 2012.
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Cite this: 'New Standard of Care' in Prostate Cancer With Bone Metastases - Medscape - Feb 01, 2012.