Michael Gnant, MD, Medical University of Vienna, discusses findings from a study exploring long-term outcomes of adjuvant treatment with denosumab among patients with breast cancer receiving aromatase inhibitors. Treatment with adjuvant denosumab was associated with markedly reduced incidence of treatment-induced clinical fractures.

These findings were presented at the 2022 ASCO Annual Meeting.

Transcript:

Hello, I'm Michael Gnant. I'm a professor of surgery at the Medical University of Vienna in Vienna, Austria, and I am the President of the Austrian Breast and Colorectal Cancer Study Group that conducted the ABCSG-18 trial.

At this year’s ASCO, I was privileged to have the opportunity to present the long-term outcome data of ABCSG-18. That's a prospective, randomized trial of adjuvant denosumab for postmenopausal patients with hormone receptor-positive breast cancer, who are treated with aromatase inhibitors.

The background of this is that aromatase inhibitors are standard of care for these patients, but we know that the main side effect of these drugs is that they can impair bone health. And in the past, bone-targeted agents have already been used, particularly bisphosphonate, in order to counteract these negative side effects of the endocrine treatment that our patients need. A little bit more modern than bisphosphonate is the more targeted anti-RANK ligand antibody denosumab that is also used at a much higher dose for the treatment of bone metastases of breast cancer or prostate cancer for that matter.

However, we tried to use denosumab in early breast cancer. Number one, to see whether that would actually decrease the number of fractures caused by the endocrine treatment, and second, to investigate the long-term outcome effects of the antibody.

This is what ABCSG-18 is all about, it's prospectively randomized, double blind, placebo-controlled phase three trial that started in the year 2006 and 3425 patients were randomized. They all were postmenopausal, had hormone receptor-positive breast cancer, early breast cancer, and were all on aromatase inhibitors.

The primary end point results actually were reported previously because that was time to clinical fracture, and in fact, essentially what we saw back in 2015 was that the antibody treatment cut fractures in half. This in itself is already a very good result. And the other thing that's good about this treatment is that at the dose and schedule we were using the antibody, that's just 60 mg twice yearly, a subcutaneous shot, more or less, so this is much less invasive than many of other of our breast cancer treatments.

Now because of that very dramatic fracture result, the IDMC back then recommended that we would offer patients who were still in the blinded phase if they want to be unblinded. And if so, that was about 16% of patients who choose to be unblinded and the total of 252 of these patients who turned out to have been on placebo opted for active denosumab treatment, which is a crossover in the trial that makes it a little bit challenging to correct for this in the long-term results. And I'm presenting a number of statistical modeling in trying to correct for this crossover.

Even the main analysis, so that's intention to treat which is obviously more conservative than any corrected modeling, already shows that also the long-term outcomes are beneficially affected. In detail, in disease-free survival, which was the first of the secondary end points, we observed the hazard ratio of 0.83. That means a 17% improvement in disease-free survival, which translates, for example, in a 4.5% absolute difference at 9 years. Just to put this in perspective, for luminal breast cancer this is about twice as much in terms of magnitude of the effect compared to aromatase inhibitors vs tamoxifen that led to a new standard of care.

Another end point we are now able to investigate is bone metastasis-free survival, very similar results, hazard ratio of 0.8, so another over 4% absolute reduction in the occurrence of bone metastasis. And I think this is important, the last endpoint of the trial, which is overall survival, was also affected in the same way. So hazard ratio of 0.8, that means 20% fewer patients dying in the trial long term.

In summary, I think that in addition to the very dramatic reduction in fractures, we can now say that adjuvant denosumab also improves disease-free survival, bone mets-free survival and overall survival, and this comes at a very low cost in terms of toxicity but we were particularly looking for osteonecrosis of the jaw, that's a rare condition associated with bone-targeted treatments, and we did not observe a single case, which is probably due to the low dose and low intensity of this treatment.

Taking all this together, I believe that adjuvant denosumab at 60 mg twice yearly should be considered a standard of care for postmenopausal breast cancer patients with hormone receptor-positive disease on aromatase inhibitors.

Source:

Gnant M, Frantal S, Pfeiler G, et al. Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial. Presented at: ASCO Annual Meeting; June 3-7, 2022. Chicago, IL, and virtual. Abstract 507.