Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer. In this stage, the cancer no longer responds to standard hormone therapies and has spread from the prostate to other parts of the body. Bone is the most common site of metastasis, which can lead to pain and other complications.
Two treatments for mCRPC are Zytiga (abiraterone acetate) and Xofigo (Radium Ra 223 dichloride). These therapies function in different ways, as Zytiga is a hormonal therapy that systemically reduces the production of androgens that fuel cancer growth. Radium-223 is a targeted radiopharmaceutical that seeks out bone metastases. Given their distinct approaches, researchers investigated combining them, and this article explores the clinical findings that explain why this combination is not used today.
Understanding Zytiga and Radium Ra 223
Zytiga (abiraterone acetate) is an androgen biosynthesis inhibitor that stops the production of androgens, like testosterone, which prostate cancer cells use for growth. While initial hormone therapies target the testes, cancer cells can eventually use androgens produced in the adrenal glands and the tumor itself.
The medication works by blocking a specific enzyme known as CYP17A1. This enzyme is present in the testes, adrenal glands, and prostate tumor tissue and is involved in the pathway that creates androgens. By inhibiting CYP17A1, Zytiga cuts off this alternative fuel supply, slowing the cancer’s progression. It is administered as a daily oral pill, often with the steroid prednisone to manage side effects.
Radium Ra 223 dichloride (Xofigo) operates on a different principle as a targeted radiation therapy delivered through the bloodstream. Radium-223 is a calcium-mimetic, meaning its chemical properties are similar to calcium. Because of this, the body treats it like calcium and it is taken up by bone tissue, particularly in areas with high turnover and repair.
Bone metastases are sites of intense bone activity, making them a natural target for Radium-223. Once it accumulates in these metastatic sites, the radium emits alpha particles. These are high-energy, short-range radiation particles that cause double-strand breaks in the DNA of nearby cells. This localized damage kills cancer cells with minimal impact on the surrounding healthy bone marrow, helping to reduce bone pain.
Scientific Rationale for the Combination
The scientific rationale for combining Zytiga and Radium-223 was based on potential for synergistic action. Researchers hypothesized that attacking mCRPC with two different and non-overlapping mechanisms could be more effective than using either agent alone. The two drugs offered a dual-front attack on the disease.
Zytiga provides a systemic, body-wide approach by depriving cancer cells of the hormones they need to grow. Radium-223, in contrast, delivers a targeted strike directly to bone metastases, which are a primary source of pain and complications for patients. The theory was that these complementary actions would lead to better outcomes.
A further hypothesis was that the hormonal pressure from Zytiga might enhance the effectiveness of the radiation from Radium-223. By weakening the cancer cells systemically, Zytiga could make tumor cells within bone metastases more vulnerable to the DNA-damaging effects of the alpha particles. This idea provided the basis for initiating a large-scale clinical trial.
The expectation was that combining these therapies could delay the onset of skeletal-related problems and extend patients’ lives more than either treatment could achieve on its own. This rationale was built on the successful individual results of both drugs. The aim was to determine if their combined power was greater than the sum of their parts.
Clinical Evidence from the ERA 223 Trial
The hypothesis was tested in a large, international Phase 3 study known as the ERA 223 trial. This randomized, double-blind, placebo-controlled trial was designed to assess the effectiveness of using Zytiga and Radium-223 together. The trial enrolled 806 men with mCRPC and bone metastases who had not yet received chemotherapy.
In the trial, all participants received Zytiga plus prednisone. The patients were then randomly assigned into two groups. One group received intravenous injections of Radium-223, while the other group received injections of a placebo. Neither the patients nor their doctors knew who was receiving the active Radium-223 versus the placebo.
The study’s primary goal was to measure symptomatic skeletal event-free survival (SSE-FS). An SSE is a serious bone complication and includes events like needing radiation or surgery to the bone, a pathological fracture, or developing spinal cord compression. The trial sought to determine if adding Radium-223 to Zytiga would extend the time before patients experienced one of these events or died.
The results of the ERA 223 trial were unexpected. The study did not meet its primary endpoint, as the addition of Radium-223 to Zytiga and prednisone did not provide a significant improvement in symptomatic skeletal event-free survival. The median SSE-FS was shorter in the combination group (22.3 months) compared to the placebo group (26.0 months). Furthermore, there was no benefit in overall survival, and more deaths occurred in the combination arm when the trial was stopped.
Safety Concerns and Increased Fracture Risk
Beyond the lack of efficacy, the ERA 223 trial revealed a significant safety issue. The data showed a substantial increase in the rate of bone fractures among patients who received the combination of Radium-223 and Zytiga. This finding directly contradicted the trial’s goal of preventing skeletal complications.
The incidence of fractures was more than double in the investigational arm of the study. Approximately 29% of patients receiving the Zytiga and Radium-223 combination experienced a fracture, compared to 11% in the group receiving Zytiga and a placebo. This difference indicated that the combination was causing harm, and the trial was unblinded and stopped prematurely in 2017 because of these findings.
This heightened fracture risk was the most prominent adverse event. While other serious adverse events occurred at similar rates in both groups, the fracture signal was a clear indicator of a negative interaction between the drugs. In 2018, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued safety alerts against the concurrent use of Zytiga with Radium-223 due to the increased risk of fractures and death.
Current Treatment Guidelines and Recommendations
The results from the ERA 223 trial have directly shaped current clinical practice for treating mCRPC. Based on the evidence showing a lack of benefit and an increase in harm, the combination of Zytiga and Radium-223 is not recommended. Major oncology guideline organizations now state that this combination is contraindicated.
For patients, this means that while both Zytiga and Radium-223 are treatments for advanced prostate cancer, they should not be administered at the same time. These drugs remain effective options when used as single agents or in sequence. For example, a patient might receive Zytiga as a primary treatment and later, upon disease progression, be treated with Radium-223, but the two are not given concurrently.
A lesson from the trial was the emphasis on bone health management. An analysis of the ERA 223 data showed that using bone-protective agents, such as denosumab or zoledronic acid, was associated with a lower rate of fractures. This observation has reinforced the recommendation that men with mCRPC, particularly those receiving treatments that affect bone density, should also be prescribed a bone-protective agent to maintain skeletal strength.