Advice for healthcare professionals:
- radium-223 should only be used as monotherapy, or in combination with luteinising hormone releasing hormone (LHRH) analogues, for the treatment of men with metastatic castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastases, and who are in progression after at least 2 prior lines of systemic therapy (other than LHRH analogues) or who are ineligible for any available systemic treatment
- radium-223 dichloride is not recommended in patients with a low level of osteoblastic bone metastases or in patients with asymptomatic bone metastases only
- carefully assess the benefits and risks of treatment before deciding whether to use radium-223 in patients with mildly symptomatic bone metastases (see below)
- do not use radium-223 in combination with, or within 5 days of discontinuation of, abiraterone acetate and prednisone/prednisolone
- the combination of radium-223 with other systemic cancer therapies other than LHRH analogues is not recommended; subsequent systemic cancer treatment should not be initiated for at least 30 days after the last administration of radium-223 dichloride
- radium-223 dichloride can cause fractures — assess bone health status and risk of fractures before and during treatment and closely monitor bone health for at least 24 months after discontinuation; consider the use of bisphosphonates or denosumab to reduce fracture risk
- report any suspected adverse drug reactions to Xofigo on a Yellow Card
Background and previous communications
Xofigo▼ was authorised in the EU in 2013 for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastases.
In December 2017, following preliminary data from the ERA-223 study, we advised that radium-223 dichloride should not be used in combination with abiraterone acetate and prednisone/prednisolone until a full review was completed of the study results and the benefit and risk of the medicine (see Drug Safety Update, December 2017). In March 2018, this recommendation became a contraindication against the use of Xofigo with abiraterone acetate (Zytiga) and prednisone/prednisolone until the completion of the review (see letter sent to healthcare professionals).
The EU review has now concluded and new restrictions and recommendations have been added to the Summary of Product Characteristics and a letter sent to healthcare professionals. The reasons for these changes are outlined in the following sections.
Data from the randomised, double-blind, placebo-controlled ERA-223 trial show an increased incidence of fractures (29% versus 11%); a reduction in overall median survival (30.7 months versus 33.3 months; HR 1.195, 95% CI 0.950–1.505; p=0.13); and an increased risk of radiological non-bone progression (HR 1.376, 95% CI 0.972–1.948; p=0.07) among men receiving radium-223 in combination with abiraterone acetate plus prednisone/prednisolone (n=401) compared with men receiving placebo plus abiraterone acetate and prednisone/prednisolone (n=405), respectively. The population assessed in the ERA-223 trial were chemotherapy-naive with asymptomatic or mildly symptomatic, metastatic, castration-resistant prostate cancer.
In view of these risks, the indication for radium-223 has been restricted to men with symptomatic bone metastases and no known visceral metastases, who have received 2 previous systemic treatments for metastatic prostate cancer (other than LHRH analogues) or who cannot receive other systemic treatments.
In a subgroup analysis of another randomised, double-blind, placebo-controlled phase 3 trial (ALSYMPCA), radium-223 treatment showed no significant improvement on overall survival (versus standard of care) in men with fewer than 6 metastases (HR for radium-223 vs placebo 0.901, 95% CI 0.553–1.466; p=0.674) or with a baseline total alkaline phosphatase lower than 220 U/L (HR 0.823, 95% CI 0.633–1.068; p=0.142). The use of radium-223 is therefore not recommended in men with a low level of osteoblastic bone metastases.
In mildly symptomatic patients, carefully assess the benefit and risks of treatment, considering that high osteoblastic activity is likely to be required for treatment benefit.
New restrictions for the use of radium-223 with other systemic anti-cancer therapies
In addition to the contraindication for concomitant use of radium-223 with abiraterone and prednisone/prednisolone, radium-223 is not recommended to be initiated in the first 5 days following the last dose of abiraterone and prednisone/prednisolone. This allows for an adequate washout period for abiraterone acetate, based on its elimination half-life.
Also, it is possible that there is an increased risk of fracture and death when radium-223 is combined with other systemic cancer therapies. Therefore, combination of radium-223 with other systemic cancer therapies other than LHRH analogues is not recommended.
Data on a safe period after which systemic cancer treatment can be started following the final dose of radium-223 are limited. Based on the estimated biological half-life of radium-223 (6 days in bone and 5 days in whole body), subsequent systemic cancer treatment (including abiraterone acetate) should not be initiated for at least 30 days after the last administration of radium-223 dichloride.
New recommendations to minimise the risk of fractures
The European review concluded that radium-223, either as monotherapy or in combination with an LHRH analogue, increases the risk of fractures, especially in patients with a history of osteoporosis or in patients with fewer than 6 bone metastases.
Before, during, and after treatment, in all patients, carefully assess and monitor bone status (for example, by scintigraphy, bone mineral density) and risk of fractures (for example, presence of osteoporosis, less than 6 bone metastases, medication increasing fracture risk, low body-mass index). In men with a high baseline risk of fracture, carefully consider the benefit of treatment against the risks.
Fractures have occurred for up to 24 months after the first dose of radium-223, therefore closely monitor bone health for at least 24 months after discontinuation.
Use of bisphosphonates or denosumab has been shown to reduce the incidence of fractures in patients treated with radium-223. Therefore, consider use of these medicines before starting or resuming treatment with radium-223.
Further studies will be conducted to characterise the efficacy and safety of radium-223. The results of an observational study are expected in 2020 and those of a Phase 4 randomised double-blind study are due in 2024. Studies will look closely at the mechanisms responsible for the increased risk of fractures and possible increased mortality reported in the ERA-223 study.
Report any suspected adverse drug reactions
Please continue to report any suspected adverse drug reactions associated with Xofigo to the MHRA through the Yellow Card Scheme. When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, treatment dates, product brand name, and batch number.
Article citation: Drug Safety Update volume 12, issue 2; September 2018: 2.