Study: Treatment to reduce bone fractures also improves breast cancer survival in postmenopausal people

IN-DEPTH REVIEW OF RESEARCH
Study background

Therapies that maintain bone health, such as bisphosphonates and denosumab, have been successful in treating cancer patients with therapy-related bone loss and fracture risk. Patients treated for prostate cancer benefit from these therapies that reduce rates of bone fracture and later complications of bone breaks. A meta-analysis from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that the addition of bisphosphonates improved cancer outcomes in postmenopausal patients with hormone receptor-positive breast cancer. In this study, researchers tested the impact of denosumab on bone fractures in breast cancer patients and how it affected cancer outcomes.

Researchers of this study wanted to know

The ABCSG-18 study is an important study because it tested whether denosumab, an antibody used to help treat bone loss, could help reduce bone loss in postmenopausal women being treated with aromatase inhibitors (AI therapy). In addition, some preclinical and clinical data have shown that drugs used to treat bone loss may also have anti-cancer properties. Therefore, the leaders of the study wanted to determine whether denosumab could improve long-term outcomes for postmenopausal breast cancer patients while helping to reduce bone loss.

Populations looked at in this study

This study enrolled 3,425 participants from 58 health centers within Austria and Sweden. The participants were mostly white (99.5%); the remaining 0.5% of participants were Asian, Hispanic or Black.

Study design

This study took place between December 2006 and July 2013. About half of the participants received an aromatase inhibitor and denosumab; the other half received an aromatase inhibitor and a placebo. The study was blinded—neither participants nor their immediate providers knew who received which treatment (only researchers managing the study design had access to that information).

Patients received 60 mg of denosumab or a placebo every 6 months for 5 years. Every 6 months during treatment, investigators measured whether a patient's disease had progressed (their cancer grew) or metastasized. In addition, after 3 and 5 years of treatment, patient bone density was measured; if needed, restaging was then performed. After treatment ended, patients received follow-up care yearly to see whether their disease had progressed or metastasized. The final date for the analysis of follow-up information was September 30th, 2017.

The study reported findings in two waves: at approximately 5 years of follow-up and after 8 years of follow-up. In addition, another study used the same patient data to look at whether cholesterol-lowering drugs (statins) could also improve outcomes in these patients. The results from all three analyses are presented below.

Study findings

Bone health was better in people taking denosumab.

• Denosumab reduced bone fractures by half as compared to the placebo group.
  • At 36 months, 5% of participants in the denosumab group had a first fracture (92 fractures), and 10% of the placebo group (176 fractures).
  • At 84 months, 11% of the denosumab group experienced first fractures compared to 26% of the placebo group.
• The time to first fracture was twice as long in the denosumab group as compared to a placebo.

Fewer people taking denosumab had their cancer progress.

• In a final analysis, people taking denosumab had improved cancer outcomes and overall survival at 9 years:
  • 79% of the denosumab group were cancer-free at an average of 9 years of follow-up compared to 76% of the placebo group.
  • 89% of the denosumab group had no bone metastases compared to 86% of the placebo group after 9 years of follow-up.

Side effects of denosumab
In the safety analysis, the frequency of adverse events did not differ between the denosumab group (1,366 events, 80%) and the placebo group (1,334 events, 79%).

The main adverse events reported were joint pain (arthralgia) and AI-associated side effects.

• 25% of participants in both the denosumab and placebo groups reported joint pain.

The numbers of serious adverse events were also similar (521 vs 511—30% in each group). These suggest that most adverse events (side effects) are associated with AI therapy rather than the use of denosumab.

Context

The results from this study are the first of its kind, with no published papers looking at the effect of denosumab on breast cancer outcomes. When the first study results were released, 19 studies were registered for “denosumab” and “breast cancer,” mostly looking at metastatic breast cancer. Two other studies, the D-CARE study and the ENDEAVOR study, were similar to this study. The D-CARE study looked only at disease-related outcomes and found no effect of denosumab on cancer outcomes. Additional research is needed to understand the impact of denosumab on cancer outcomes.

Conclusions

Adding denosumab to adjuvant AI therapy reduces bone fractures and may improve cancer outcomes in postmenopausal patients with hormone receptor (HR)-positive breast cancer.

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posted 2/27/23