Study: Bone-protecting drugs cut the risks for fractures caused by metastatic prostate cancer treatments

Contents

STUDY AT A GLANCE

What is this study about?

The PEACE-III trial is an ongoing study looking at the benefit of enzalutamide (a type of hormonal therapy) alone or in combination with radium-223 dichloride (a mildly radioactive form of the metal radium) to treat metastatic castration-resistant prostate cancer (mCRPC) that has spread to the bone. Early results presented at the 2021 American Society of Clinical Oncology (ASCO) meeting showed that the addition of a bone-protecting agent, BPA, (e.g., zoledronate or denosumab) to treatment with enzalutamide alone or in combination with radium-223 (ra223) almost abolished the risk of bone fracture. While the PEACE-III trial is ongoing and the results for enzalutamide combined with radium-223 for prostate cancer are unknown as yet, it is clear that BPAs will be a key component for managing bone fractures during these types of treatments.

Why is this study important?

While the rate of prostate cancer is increasing, therapies to treat the disease are improving. Better treatments are resulting in improved quality of life and survival. However, some of these treatments may lead to the weakening of a patient’s bones, resulting in an increased risk of fracture. Because of this, bone health is emerging as one of the most important considerations for men receiving treatment for prostate cancer. There is an urgent need for increased focus on managing the bone health of men receiving prostate cancer treatments. This study includes findings about how the addition of a bone-protecting agent BPA is important for treatments that might otherwise weaken bone health.

Prostate cancer and bone metastases

Patients with metastatic prostate cancer are initially treated with medical or surgical androgen deprivation to lower the levels of androgens made in the testicles. However, most patients develop what is termed castration-resistant prostate cancer (CRPC). mCRPC generally has a poor prognosis with shortened survival.

Bones are the most common site of prostate cancer spread (or metastasis). Among patients with metastatic prostate cancer, more than 90 percent have bone metastases, which not only affects quality of life by causing significant pain but can also reduce overall survival. Almost half of mCRPC patients develop significant bone pain and skeletal-related complications such as fractures or both.

Traditional treatments for patients with mCRPC and bone metastasis, including androgen inhibitors and internal radiotherapy, can weaken bones and increase the risk for bone breaks.

PEACE-III

PEACE-III is a randomized phase III study comparing enzalutamide (an androgen inhibitor) alone versus enzalutamide plus radium-223 dichloride (a type of internal radiotherapy that is given intravenously) in prostate cancer patients with metastasis to bone. The researchers want to determine whether adding radium-223 to enzalutamide improves outcomes for these patients. It is important to note that the combined treatment of enzalutamide and Ra-223 is not FDA approved standard of care and is currently not used outside of clinical trials.  

Radium-223 is administered intravenously and delivers radiation directly to the bone; like calcium, it is taken up by the bone. Importantly, radium-223 has been shown to reduce pain and prolong survival in men with prostate cancer that has metastasized to the bone. While enzalutamide lowers male hormone levels and helps to prevent prostate cancer from returning, it can cause bone loss and osteoporosis.

An earlier study designed similarly to PEACE-III showed that combining radium-223 with another androgen deprivation therapy (abiraterone) significantly increased the rate of fractures. Because of this observation, bone protecting agents (BPAs) were mandated for all PEACE-III patients regardless of the study arm to which they were assigned.

Either zoledronate (a bisphosphonate) or denosumab (a monoclonal antibody) were given to patients participating in PEACE-III. Both drugs are bone-protective agents that prevent bone from breaking down.

Study findings

A total of 267 men with newly diagnosed mCRPC were randomly assigned to one of two groups:

• enzalutamide alone (133 patients)
• enzalutamide plus radium-223 (134 patients)

136 patients enrolled in PEACE-III after BPAs were mandated and were given a bone-protecting agent (e.g., zoledronate or denosumab) regardless of whether they were in the enzalutamide only group or the enzalutamide plus radium-223 group.

At 12 months:

• Among patients in the enzalutamide plus radium-223 arm, bone fractures occured in 37% of those who did not receive a BPA compared to 3% of patients who received a BPA.

• Among patients in the enzalutamide alone arm, bone fractures occurred in 16% of patients who did not receive a BPA compared to 3% in patients who did receive a BPA.

Results were similar at 24 months:

•  Among patients in the enzalutamide plus radium-223 arm, bone fractures occurred in 52% of patients who did not receive a BPA compared to 4% in patients who received a BPA.

• At 12 months, among patients in the enzalutamide alone arm, bone fractures occurred in 22% of patients who did not receive a BPA compared to 3% in patients who did receive a BPA.

This updated analysis of PEACE-III confirms that in absence of BPAs, the risk of fracture is significantly increased when radium-223 is added to enzalutamide. However, this risk is almost abolished by the use of BPAs, thus stressing the importance of giving BPAs to mCRPC patients.

At this time, no outcome data have been reported for PEACE-III for how enzalutamide with or without radium-223 impacts prostate cancer progression.

Strengths and limitations

Strengths

• This updated analysis confirms that the addition of radium-223 to an androgen inhibitor enzalutamide increases the risk of fracture.
• This study shows that adding a BPA (e.g., zoledronate  or denosumab) to treatment with radium-223 can effectively reduce the risk of fracture. 

Limitations

• This study is ongoing. Whether the combination of enzalutamide with radium-223 improves cancer outcomes will not be known for some time.
• The racial or ethnic diversity of participants was not reported. Treatment response may differ by race and ethnicity.   
• More research is needed to determine the optimal time patients should consider treatment combined with a BPA.

What does this mean for me?

Bone loss and fracture are well-known side effects of treatment for metastatic prostate cancer. If you are receiving androgen deprivation therapy with or without Radium-223 for treatment of mCRPC, you might want to ask your doctor about your risk of bone fracture while taking these medications and whether adding a BPA may be beneficial.

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posted 11/5/21

Reference

Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACE-III trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. American Society of Clinical Oncology Annual Meeting. Abstract 5002.

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.