Use of the novel radiopharmaceutical radium-223 dichloride (Xofigo, Bayer) in prostate cancer that has metastasized to the bone should be restricted, according to the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC).
PRAC first noted concerns about this product in December 2017, as reported by Medscape Medical News. At the time, the committee noted that it was investigating reports of an increase in deaths and fractures in an ongoing trial exploring the radiopharmaceutical for an unapproved use.
Now PRAC has said that it decided, following a review of those data, to recommend restricting the use of radium-223 dichloride to patients who have had two previous treatments for metastatic prostate cancer that has spread to the bone or who cannot receive other treatments.
PRAC also confirmed its previous interim recommendation that the radium-233 dichloride must not be used in combination with abiraterone acetate (Zytiga, Janssen) and prednisone/prednisolone.
In the trial under review, patients who received radium-223 dichloride in combination with abiraterone acetate and prednisone/prednisolone died 2.6 months earlier on average than those given placebo with abiraterone acetate and prednisone/prednisolone. "In addition, 29% of patients who received the Xofigo combination had fractures, compared with 11% of patients given placebo," the EMA explained.
However, patients with no or only mild symptoms were included in the trial, but radium-223 dichloride is only approved for use in patients with symptoms, the agency pointed out.
The agency noted the theory that radium-223 dichloride, which is absorbed by the bone, accumulates at sites where there is already bone damage, such as with osteoporosis or microfractures, which may increase fracture risk. "However, the reasons for a possible earlier death in this study are not fully understood," the EMA commented.
The EMA noted that Bayer, the company that markets Xofigo, has been asked to conduct studies to investigate, in particular, the mechanisms responsible for the possible risk for earlier death and the increased fracture risk reported in the study. The benefits and risks of radium-223 dichloride in the restricted indication should also be further characterized.
Guidance on Product Use
The EMA reminded clinicians that radium-223 dichloride should not be used in patients who have no symptoms, in line with the current indication, or in those with a low number of bone metastases called osteoblastic bone metastases. The agency also stated that radium-223 dichloride should not be used with other systemic cancer therapies, except for hormone therapies.
Patients should be carefully assessed for their risk for fractures before, during, and after treatment, the agency said. Preventive measures, such as the use of bisphosphonates or denosumab as agents to increase bone strength, should be considered before treatment with radium-223 dichloride is started or resumed.
The PRAC recommendations will now be sent to the EMA's Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which will adopt the Agency's opinion.
Radium-223 dichloride is currently approved for use in the treatment of castration-resistant prostate cancer in patients who have symptomatic bone metastases.
The product has been on the market for about 5 years. It was approved in the United States in May 2013 by the Food and Drug Administration and approved in Europe in November 2013.
Favorable Benefit/Risk Ratio When Used as Approved
Also in December 2017, the manufacturer of the radiopharmaceutical, Bayer, announced in a press statement that the trial had been unblinded on the recommendation of an independent data monitoring committee (IDMC).
"The IDMC recommendation is due to the observation of an imbalance of more fractures and deaths in the treatment arm investigating radium-223 in combination with abiraterone acetate and prednisone/prednisolone," the company said.
"Patient safety is our top priority. We are therefore unblinding the study to thoroughly analyze the data," said Mike Devoy, chief medical officer at Bayer.
"It is important to note that, based on available data from previous trials as well as real-world use, the benefit-risk profile of Xofigo in its approved indication remains favorable," he added.
Further details are available on the EMA website.
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