SAN ANTONIO—Researchers on the Phase III ABCSG-18 clinical trial say that denosumab, most commonly used to treat osteoporosis, should be offered to all postmenopausal patients with early-stage HR-positive breast cancer receiving adjuvant aromatase inhibitor therapy, irrespective of their bone health status, because adding denosumab increased disease-free survival in that trial.
Results of the prospective, randomized, double-blind, placebo-controlled, Phase III trial, supported by Amgen, were presented at the San Antonio Breast Cancer Symposium on behalf of the Austrian Breast and Colorectal Cancer Study Group by Michael Gnant, MD, Professor of Surgery at Medical University of Vienna (Abstract S2-02).
Disease-free survival in the intent-to-treat analysis at seven years was 83.5 percent for patients in the denosumab arm versus 80.4 percent for patients on placebo.
The disease-free survival benefit at seven years was even greater among patients with tumors greater than 2 cm: 80.3 percent for denosumab versus 69.8 percent for placebo.
“This benefit comes in addition to significantly reducing clinical fractures and improving bone mineral density,” Gnant said.
Also, there were no measurable differences in adverse events between adjuvant denosumab and placebo, including no cases of confirmed osteonecrosis of the jaw or of atypical fracture.
Among the 3,425 postmenopausal patients with early-stage, HR-positive breast cancer enrolled in ABCSG-18, 1,711 were randomly assigned to receive 60 mg of subcutaneously administered denosumab once every six months and 1,709 were randomly assigned placebo.
‘Amplifies Earlier Benefit’
An earlier report from ABCSG-18 showed that denosumab reduces the risk of clinical fractures by 50 percent in postmenopausal women with breast cancer receiving aromatase inhibitors, and that it can be administered without added toxicity (Gnant et al: Lancet 2015;386:433-443).
“The new finding reported here amplifies the benefit of adjuvant denosumab—a benefit that is at least comparable to the disease-free survival benefit of adjuvant bisphosphonates.”
Gnant noted that this analysis was performed as a result of a recommendation from the Independent Data Monitoring Committee and was based on only 370 disease-free survival events.
Still, Needs Longer Follow-up
“Therefore it does not provide perfectly undisputable statistical power, and will have to be confirmed by future analyses with longer follow-up,” he said. “I do not, however, have any doubt about the validity of the results, given the fact that the outcome benefits show clearly so early in the follow-up and are numerically bigger than we have seen in the past with bisphosphonates.”
He also said the monitoring committee recommended a “patient's choice” unblinding of the placebo-controlled trial, to occur in 2016, when eligible trial patients will be offered the option of treatment with denosumab for two more years if they were in the placebo group.
At a news conference, Gnant said he would be putting his new breast cancer patients on denosumab.
Why not Commonly Used?
It is clear from numerous clinical studies that in postmenopausal women, bisphosphonate treatment improves both disease-free and overall survival, said the moderator of the news conference, Virginia G. Kaklamani, MD, Professor of Medicine in the Division of Hematology/Oncology at the University of Texas Health Science Center at San Antonio, and leader of the Breast Cancer Program at the Cancer Therapy & Research Center.
“And now we have the denosumab data, but we don't use these for our patients in the clinic! What are we missing, what can we do for these patients to improve their outcomes?”
She said the issue with denosumab is that there is only disease-free survival benefit and not overall survival data yet.
“But with the bisphosphonates there is—and many studies have shown in postmenopausal women that there is a benefit.”
For that matter, she said, bisphosphonates are not the standard of care for breast cancer patients in the U.S. because the Food and Drug Administration has not approved them. And that, she said, is because most studies found benefit of bisphosphonates in postmenopausal women who were a subset of a study that included both pre- and post-menopausal women.
“Any time you look at a subset population of a whole study you are always afraid that the statistics are not going to be right because the study is not powered to show that,” she said.
Kaklamani said Gnant's earlier study showed a benefit in postmenopausal women, but it included premenopausal women who were given ovarian suppression and made menopausal, so again that is not a pure postmenopausal population.
“Now this latest study is in postmenopausal women. But denosumab is an extremely expensive drug, and I doubt any insurance company would pay for it, especially when we don't have overall survival data.
“We need two or three more studies pointing in the same direction so we can go to the FDA and say ‘please approve this.’”
Kaklamani said she compensates by finding any excuse to put postmenopausal breast cancer patients taking aromatase inhibitors on bisphosphonates—“osteoporosis, osteopenia, anything.”