XOFIGO APPROVED BY EMA

The novel radiopharmaceutical radium-223 (Xofigo, Algeta & Bayer) has now been approved by the European Commission, following a positive opinion in September. This approval allows marketing of the product in all 28 countries of the European Union (EU), as well as in Norway, Iceland, and Liechtenstein, following national approval there.

The product is already available in the United States, having been approved there in May 2013.

The novel product (previously known as Alpharadin) contains the alpha particle–emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The alpha particles have high energy, which results in an antitumor effect on the bone metastases, but a short range, which limits damage to surrounding tissue.

The product is indicated for use in men with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastases. The approval is based on results from the pivotal phase 3 ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, which showed a survival advantage and was stopped early because of benefit.

The ALSYMPCA trial was conducted in 809 patients with prostate cancer who were resistant to hormone treatment and had developed 2 or more bone metastases. All participants received standard treatment, but the men who also received radium-223 chloride lived significantly longer. An interim analysis revealed a median overall survival of 14.0 months, compared with 11.2 months (hazard ratio, 0.695; P = .00185), and an updated analysis later confirmed this benefit.

When these results were first reported at international meetings, experts hailed them as "practice changing" and said that the product should be considered "a new standard of care." The trial has since been published (N Engl J Med. 2013;369:213-223), and the product was described as addressing "an unmet need."

Commenting now on the EU approval, principal investigator of the ALSYMPCA trial, Christopher Parker, MD, from the Royal Marsden Hospital, London, United Kingdom, said the product is "an exciting advance in the treatment of prostate cancer."

Prostate cancer often spreads to bones, and bone metastases lead to pain, fractures, and other complications that can significantly impair the patient's health and well-being, he said in a statement. Radium-223 targets the bone metastases, delivering a localized effect to prolong patient survival, he added.

Details of Adverse Events

When the ALSYMPCA trial was published, the trialists highlighted "the excellent safety profile of radium-223." They noted that the rates of 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%).

Now, in a press release announcing the EU approval, Bayer gives further details of the adverse events.

The most common adverse reactions in the radium-223 and placebo groups, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%).

Grade 3 and 4 adverse events were reported in 57% of radium-223–treated patients and 63% of placebo recipients.

The most common hematologic laboratory abnormalities in the radium-223 and placebo groups, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%).

The manufacturer also provides further details on some of the complications that were observed.

In the randomized trial, 2% of patients in the radium-223 group experienced bone marrow failure or ongoing pancytopenia compared with no patients in the placebo group. Two patients died of bone marrow failure. For 7 of 13 patients treated with radium-223, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent of the radium-223 group and 2% of the placebo group permanently discontinued therapy because of bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of radium-223–treated patients compared with 0.3% of patients receiving placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1 and="" for="" nbsp="" p="" patients="" placebo.="" radium-223="" receiving="" similar="" those="" treated="" was="" with="">

The manufacturer recommends that clinicians closely monitor any patients with evidence of compromised bone marrow reserve and should provide supportive care measures when clinically indicated.

In addition, the manufacturer recommends monitoring blood counts at baseline and before every dose of radium-223.