Radium-223 in Prostate Cancer Addresses 'Important Unmet Need'

Zosia Chustecka

July 17, 2013

The novel alpha-emitting product radium-223 (Xofigo, Algeta/Bayer), approved recently in the United States for use in prostate cancer with bone metastases, addresses an "important unmet need," say researchers reporting results from the phase 3 trial that led to the product's approval.

Final results from that trial, known as Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA), were published in the July 18 issue of the New England Journal of Medicine.

The trial was stopped early after an interim analysis showed that treatment with radium-223 significantly improved survival, compared with placebo. When these early results were originally presented, they were hailed by experts as practice-changing and were considered a new standard of care.

The updated analysis has confirmed a median survival advantage of radium-223 over placebo (14.9 vs 11.3 months; hazard ratio [HR], 0.70; P < .001).

The ALSYMPCA trial involved 921 men with castration-resistant prostate cancer (CRPC) and at least 2 bone metastases (but no visceral metastases). Patients were enrolled whether or not they had received previous docetaxel therapy.

Many patients with CRPC and bone metastases do not receive docetaxel because they are too frail, have a pre-existing condition that precludes its use, or simply decline treatment, note lead author Christopher Parker, MD, from the academic urology unit at the Royal Marsden Hospital in Surrey, United Kingdom, and colleagues.

"Our study addressed this important group by including patients who were not thought to be eligible to receive chemotherapy, or who chose not to receive it," they note. They estimate that around 20% to 40% of patients with CRPC and bone metastases never receive chemotherapy, so "our study addresses an important unmet need in a population that is not served by current therapies," they explain.

Because the control group received placebo plus the best standard of care, these findings could be generalizable to routine clinical practice, the researchers note.

The survival advantage was similar in patients not previously treated with docetaxel and in those who were.

Of the 395 patients not previously treated with docetaxel, 262 were randomized to receive radium-223 and 133 to receive placebo. In this cohort, median overall survival was longer with radium-223 (16.1 vs 11.5 months; HR, 0.74).

Of the 526 patients previously treated with docetaxel, 352 were randomized to receive radium-223 and 174 to receive placebo. In this cohort, median overall survival was also longer with radium-223 (14.4 vs 11.3 months; HR, 0.71).

Excellent Safety Profile

Dr. Parker and colleagues note that, since the ALSYMPCA trial began, a number of new drugs have been approved for use in prostate cancer after docetaxel treatment, including cabazitaxel (Jevtana, sanofi-aventis), abiraterone (Zytiga, Cougar Biotech), and enzalutamide (Xtandi, Astellas).

"The excellent safety profile of radium-223 and the nonoverlapping mechanism of action make radium-223 potentially suitable for use either sequentially or in combination with these other agents," they write.

Overall and serious adverse events were consistently lower with radium-223 than with placebo. In addition, there was no clinically meaningful difference in the frequency of grade 3/4 adverse events between the radium-223 and placebo groups (56% vs 62%).

Serious adverse events in the radium-223 and placebo groups included disease progression (11% vs 12%), bone pain (10% vs 16%), anemia (8% vs 9%), and spinal cord compression (4% vs 5%).

In addition, meaningful improvement in quality of life was better with radium-223 (25% vs 16%; P = .02).

This "remarkable tolerability" of radium-223 is highlighted in an accompanying editorial by Neha Vapiwala, MD, and Eli Glatstein, MD, from the Department of Radiation Oncology at the Perelman School of Medicine, University of Pennsylvania, in Philadelphia. They note that the compound is "safe and manageable for both patients and providers."

"Radium-223 will both complement and contend with existing therapies," the editorialists write. "While its most appropriate 'fit' is actively investigated, the first-line role of taxanes in metastatic CRPC may be re-examined."

Breakthrough Product

In an interview with Medscape Medical News, Dr. Vapiwala pointed out that radium-223 is the first alpha-emitter to reach the market, and described it as a "breakthrough for radiopharmaceuticals" and "another breakthrough for prostate cancer," as it joins several other agents that have recently been approved for this disease.

Radium-223 has an "elegant way of working," she said. Its similarity to calcium means that it naturally travels to the bone; once there, it releases short-range high-energy alpha particles that are cytotoxic mainly through double-stranded DNA breaks. The alpha particles do not travel far, so damage to other tissue is minimized, and because the half-life of radium-223 is short (roughly 11 days), radioactivity decays rapidly.

This means there are no special precautions needed, Dr. Vapiwala explained. Any leftover drug soon becomes inactive and can be thrown away with regular waste, patients do not have their contact with others restricted, and no special shields or equipment are required for providers. There is no need for any major additional investment for hospitals that have existing radionuclide capabilities, and the product can be administered by radiation oncologists or nuclear medicine physicians after some tailored/specialized training.

The safety of the product and the fact that it was so well tolerated by patients are important because some cancer treatments can make patients feel worse and diminish their quality of life, she explained. In addition, this product improved survival and provided symptom control and pain relief, and it was shown to do so in a clinical trial that reflects patients in the real world. "What is nice about this study is that the patients truly resembled what we see in clinical practice."

"The real-world applicability of this new therapy is undeniable," Dr. Vapiwala said in a statement. "Hormone-refractory prostate cancer that has metastasized to the bones can be a debilitating and, in many cases, life-threatening battle. The addition to our armamentarium of this well-tolerated bone-targeted therapy that helps to not only relieve symptoms but also extend lives is an incredibly important development for the 30,000 men who are facing death from prostate cancer each year and for all of the individuals who care for them. It is also a seminal event in the realm of alpha-emitter therapy, opening a new door for more research into this class of agents that has great potential in other areas of oncology."

The same point was made by Marc Garnick, MD, clinical professor of medicine at the Beth Israel Deaconess Medical Center in Boston, and editor-in-chief of the Annual Report on Prostate Diseases. The study design was notable because it allowed patients to simultaneously receive the best standard of care, meaning that the results are applicable "to a broad population of castrate-resistant prostate cancer patients," he told Medscape Medical News.

"The investigators also honed in on improving symptomatic bone and skeletal events, rather than some arbitrarily defined nonsymptomatic osseous radiographic evaluation," Dr. Garnick explained. "Since bone disease is the predominant site of metastases and the overwhelming cause of disease-related morbidity and mortality, a targeted radiopharmaceutical is of great benefit and illustrates that an agent that targets the metastases can actually lead to an overall improvement in survival, with safety parameters that are totally tolerable and seem to lessen once the drug is administered."

"While the study excluded those with visceral metastases, based upon the safety profile, I would not envision many eligibility restrictions on its use," he continued. There is a real possibility that radium-223 will eventually be moved earlier and earlier to first-line therapy in patients with either castrate-sensitive or castrate-resistant disease and osseous metastases, he added, echoing the sentiments of the researchers and the editorialists.

"This radiopharmaceutical is very impressive," Dr. Garnick concluded. "Kudos to all involved in this study."

The study was supported by Algeta and Bayer Pharmaceuticals, the manufacturers of radium-223.

N Engl J Med. 2013;369; 213-223, 276-278. Abstract, Editorial


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