Combining radium-223 (Xofigo) with Abiraterone (Zytiga) is not recommended.

[Wendy_Winnall]

Radium-223 (Xofigo) and Abiraterone (Zytiga) are two treatments used by Australian men with metastatic prostate cancer. Both are relatively effective and have acceptable side effect profiles. They work using different mechanisms of action. So it’s tempting to predict that taking both at once would be even better than taking one. However, results from a large clinical trial have now shown that this is a dangerous approach.

Sometimes, combining treatments works well. But we can’t assume that it will. Unfortunately, long and expensive clinical trials are necessary to ask whether we should be combining two treatments for metastatic prostate cancer. The latest results from an international trial combining Abiraterone and radium-223 are an important lesson; sometimes combined treatments lead to harm. Predicting when this will happen is a difficult task, so it must be tested properly in trials.

Abiraterone (Zytiga)

Abiraterone is a new type of anti-androgen drug. It stops male hormones (androgens) being produced by the testicles, adrenal glands and the prostate tumour cells. Abiraterone improves the average survival time for men with metastatic prostate cancer.

In Australia, Abiraterone (with prednisone or prednisolone) is approved by the TGA for treating patients with:

- newly diagnosed high-risk metastatic hormone sensitive prostate cancer in combination with androgen deprivation therapy (ADT), or

- metastatic castration resistant prostate cancer (mCRPC) who have no symptoms or mild symptoms after failure of ADT, or

- with mCRPC who have received prior chemotherapy containing a taxane.

Radium-223 (Xofigo)

Radium-233 is a treatment that releases radioactive particles within the body. It specifically binds to and releases this radiation into prostate tumours in within bones. This damages the prostate cancer cells growing there, as well as the bone cells.

It may sound surprisingly that there are cells in the bones. These include bone marrow cells, and cells called osteoclasts and osteoblasts. The latter two are involved in the formation of new bone material. Bones are constant remodelled and replaced during our lifetime. As we get older, this process doesn’t work as well as it should, contributing to weakened bones. Unfortunately for prostate cancer patients, hormone therapy (Androgen deprivation therapy, ADT) and tumours that spread to the bones can also lead to bone damage.

Radium-223 improves survival times and delays the onset of major bone problems for men with bone metastases in clinical trials. Radium-223 is approved by the TGA for treatment of patients with castration resistant prostate cancer with symptomatic bone tumours but no known metastatic tumours in internal organs.

Combination therapy with both treatments

Researchers and clinicians have proposed that a combination of radium-223 and Abiraterone would be a safe and effective treatment for mCRPC. The two treatments have quite different mechanisms of action. Therefore, it’s feasible that a combination of the two would work better than just one at a time.

Previous small-scale trials indicated that a combination of radium-223 and Abiraterone would be safe and effective for men with mCRPC. This has now been tested in a large international clinical trial called ERA 223.

The ERA 223 clinical trial

Results from the ERA 223 clinical trial have recently been published in a top journal, Lancet Oncology. The aim of ERA 223 was to test whether men with mCRPC having radium-223 with Abiraterone lived for longer without bone symptoms than men having Abiraterone alone. In other words, does adding radium-223 to Abiraterone improve treatment? The trial tested both the safety and benefits of the combination.

The first author of the scientific publication was Prof Matthew Smith from the Massachusetts General Hospital Cancer Centre, US, and the senior author was Prof Celestia Higano from the Fred Hutchinson Cancer Research Center in the US. Many different researchers were involved, from regions such as Europe, US, UK, Canada, Singapore, Russia, Brazil, Japan and Israel. The ERA 223 trial recruited 806 men from 165 different oncology centres over 19 countries.

ERA 223 is a gold-standard trial that aims to provide the highest level of evidence. It’s a phase 3 randomised controlled trial conducted at sites in 19 different countries. This is a placebo-controlled trial, where men did not know if they were receiving radium-223 or a placebo. It’s also a “blinded” trial, where the researchers collecting data did now know who had the placebo or radium-223 during data collection.

Men who volunteered for this trial had mCRPC that included tumours spread to the bones. They were men who had not yet had chemotherapy. All 806 of the men in the trial received Abiraterone treatment for their prostate cancer. They had this treatment as a tablet once a day, in combination with either prednisone or prednisolone (anti-inflammatory drugs). 401 men were randomly assigned to receiving radium-223. They had up to 6 injections of radium-223 with 4 weeks in-between treatments. 405 men were randomly assigned to receive placebo treatments, having injections that didn’t contain radium-223.

Was adding radium-223 to Abiraterone effective?

The main outcome measured in this trial was called symptomatic skeletal event-free survival. This is defined as the time until each man either died or developed bone problems, such as fractures or pain that needed radiotherapy treatment. The researchers used this measure to ask whether the treatment either increased survival times, or at least increased the time in which men were living without major complications from their bone tumours.

Unfortunately, there was no improvement in the main outcome for men having radium-223 in addition to Abiraterone, compared to men having Abiraterone alone. When the trial was stopped, 49% of men having combination treatment either experienced skeletal events or had died, compared to 47% of men having Abiraterone alone. Men having combined treatment had an average skeletal event-free survival period of 22.3 months. This was similar to the average skeletal event-free survival period of 26 months for men having Abiraterone alone.

The trial also measured outcomes such as overall survival and the need for treatments such as chemotherapy. These measures did not show any significant differences between the two groups. These results provide further evidence that adding radium-223 to Abiraterone was not beneficial.

The ERA trial has therefore found no evidence that adding radium-223 to Abiraterone improved the benefits of this treatment for men with mCRPC with bone tumours.  

Was adding radium-223 to Abiraterone safe?

There were increased side effects when radium-223 was added to Abiraterone. 29% of men having the combination treatment suffered fractures compared to 11% having Abiraterone alone. The rate of serious fractures was also higher, at 9% for the combined treatment versus 3% for men with Abiraterone alone.

So the ERA 223 trial showed that adding radium-223 to Abiraterone increased the side effects (fractures) for men with mCRPC, with no benefit in treating the cancer.

Why did fractures increase?

This increase in fractures was quite unexpected. Radium-223 treatment usually improves the rate of fractures. We don’t really know why this has happened.

Prostate tumours that have spread to bones cause small holes to develop in the bones, called lytic lesions. Lytic lesions weaken the bones. Treatments such as ADT and prednisone can also weaken the bones, causing fractures. Results from the ERA 223 trial indicate that osteoporosis-like fractures have been the ones to increase. These fractures are more likely to be the result of older age, falls, ADT or prednisone treatment. The study indicates that the combined radium-223 and Abiraterone treatment has increased the risk of osteoporosis-like fractures.

A warning for men with metastatic prostate cancer and their doctors

On March 9^th 2019 it was announced that 34.7% of the men receiving combined treatment in this trial had now died, compared to 28.2% of the men who had Abiraterone alone. The European Medicines Agency (EMA) has issued a formal warning against using radium-223 in combination with Abiraterone (plus prednisone or prednisolone) in patients with metastatic prostate cancer because of an increased risk of death and fractures. This is an important lesson for all, and reinforces the need to test various combinations of drugs properly before they can be recommended. Just because two different treatments are safe and effective, does not mean that taking them at the same time will be a safe and effective combination.

This warning only applies to the combined treatment with radium-223 and Abiraterone. It shouldn’t affect use of these drugs individually, which is the case for the majority of men receiving treatment in Australia.