US FDA approves radium-223 dichloride for treatment of men with mCRPC

The “New” Prostate Cancer InfoLink apologizes for a delay in letting readers know that on Wednesday the US Food & Drug Administration approved radium-223 dichloride (Xofigo®) for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, but no known visceral (i.e., soft tissue) metastases.

The results of the Phase III clinical trial of radium-223 dichloride were originally reported on this web site in September 2011, and the drug has been available to patients through an expanded access clinical trial for

The following message was sent out yesterday to its members by the American Society of Clinical Oncology, in cooperation with the director of the FDA’s Office of Hematology and Oncology Products:

On May 15, 2013, the U. S. Food and Drug Administration approved radium Ra 223 dichloride (Xofigo Injection, Bayer HealthCare Pharmaceuticals Inc.) for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.  Xofigo is an alpha-particle emitting radiotherapeutic drug which mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases.

The approval was based on a double-blind, randomized, placebo-controlled trial in patients with metastatic castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.  Patients were allocated 2:1 to Xofigo, 50 kBq/kg (1.35 microcurie/kg), intravenously, every 4 weeks for 6 cycles plus best standard of care (N = 541) or to matching placebo plus best standard of care (N = 268).  Best standard of care included local radiotherapy, corticosteroids, anti-androgens, estrogens, estramustine or ketoconazole.  All patients were to continue androgen deprivation therapy.  The median age was 71 years, 94% were Caucasian, 86% had an ECOG performance status of 0-1, and 58% had received prior docetaxel.  Fifty-four percent of patients used opiate and 44% used non-opiate pain medications.   Overall survival (OS) was the primary endpoint.

At the pre-specified interim analysis, a statistically significant improvement in OS was demonstrated [HR 0.70 (95% CI: 0.55, 0.88), p = 0.00185].  The median OS was 14.0 and 11.2 months in the Xofigo and placebo arms, respectively.  The improvement in OS was supported by a delay in time- to- first symptomatic skeletal event favoring the Xofigo arm.

The most common (greater than or equal to 10%) adverse reactions in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema.  The most common (greater than or equal to 10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.  Two percent of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia.  No patients on the placebo arm experienced bone marrow failure or pancytopenia.

The recommended dose and schedule for Xofigo is 50 kBq/kg (1.35 microcuries/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses.

Full prescribing information for radium-223 dichloride is available on the FDA’s web site. The contact phone number for patient support services (for those who may need assistance in covering costs of treatment or for other information) is 1-855-6XOFIGO (1-855-696-3446). Very basic information about the use of this drug is available at a product-specific web site. This information will undoubtedly be expanded relatively quickly.

The “New” Prostate Cancer InfoLink would note for patients that radium-223 dichloride is the first drug of its type (an alpha-particle emitting radiotherapeutic agent) ever to be approved for the treatment of any disorder. For appropriate patients its use is most likely to be recommended and prescribed by medical oncologists (as opposed to urologists or even urologic oncologists), but treatment with this drug would almost always need to be carried out by appropriately qualified radiation oncologists or specialists in nuclear medicine.

Patients treated with radium-223 dichloride during clinical trials were all receiving other forms of “best standard of care” at the time the trials were conducted, but these forms of care did not include either abiraterone acetate (Zytiga) or enzalutamide (Xtandi), which were investigational drugs at the time that radium-223 dichoride was being tested. We therefore do not know whether men who have already been treated with either abiraterone acetate or enzalutamide (or both) will necessarily demonstrate a survival benefit when treated with radium-223, or whether either of these two drugs might have greater benefit when combined with treatment with radium-223. Furthermore, patients treated in the Phase III trial of radium-223 may or may not have received prior docetaxel-based chemotherapy.

We should also note that radium-223 was previously known by the brand name Alpharadin (as opposed to Xofigo), and so early data on the clinical development of this drug is often presented using this name.

Radium-223 will be marketed in the USA by Bayer Healthcare and by the original developer (Algeta, Inc.) Media releases from Algeta and from the US-based pharmaceutical division of Bayer Healthcare are available on line.

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