Expanding Therapeutic Options for Breast Cancer - Episode 8
Joyce A. O’Shaughnessy, MD: Let’s discuss other adjuvant data and the importance of the adjuvant denosumab data. There is the long-awaited D-CARE trial and an update on ABCSG-18. Komal, could you summarize those for us?
Komal Jhaveri, MD, FACP: Yes. We obviously know where denosumab is indicated and use that very comfortably. We know that we use that in our patients with bone loss in the early-phase setting. We know we use it in patients in the palliative setting for preventing skeletal morbidities. The question is, can we use these agents to improve outcomes in early-stage setting? They set out to answer that question, at least as a secondary endpoint, in the updated data from the ABCSG-18 trial, and it was the primary endpoint of the D-CARE trial that you just mentioned. Both showed conflicting results. They didn’t answer this question in a straightforward way.
We heard the primary results of the ABCSG-18 trial last year. When you give a patient adjuvant denosumab, you actually reduce their risk of clinical fractures, which was the primary endpoint, by 50%. So, instead of 16%, it was 8% in that study. What they presented this year were the updated results for the secondary endpoint, which was disease-free survival benefit. What they showed at both 5 years and at 8 years was that patients who got denosumab versus placebo saw an 8% improvement in the disease-free survival. So, 81% to 89% at the 5-year mark, and the same 8% differential at the 8-year mark. This kind of suggested that when we give denosumab with an aromatase inhibitor (AI) every 6 months for 5 years, there is a disease-free survival benefit.
The D-CARE study is different than the ABCSG-18 study. The majority of those patients had received an anthracycline and a taxane-based chemotherapy regimen. Over 95% had that chemotherapy regimen. The trial is large. It’s 4000 patients. Patients were getting this chemotherapy and then were either getting denosumab or placebo. The scheduling is different from what it was in the ABCSG-18 trial. Patients got denosumab monthly for 6 doses and then used the therapy every 3 months for the remainder of their duration.
And 20% were also HER2-positive. The majority were node-positive. About 94% were node-positive. The primary endpoint was set out to be bone metastases—free survival. They saw no difference between the denosumab and the placebo arm for the primary endpoint of metastases-free survival. So, it was kind of negative.
A 5% rate of osteonecrosis of the jaw was also seen. About 122 patients developed osteonecrosis of the jaw, which probably goes with the scheduling. So, yes, based on the D-CARE study, we don’t know exactly how the adjuvant denosumab story plays out.
Sara A. Hurvitz, MD: It kind of reminds me of the early data with zoledronic acid, right? We had the ABCSG study in the premenopausal women. I think the ABCSG-6 study showed a real improvement in outcomes. Then the AZURE study came out, and I was texting my nurse practitioner, “Stop giving zoledronic acid.” It took a meta-analysis to really tell us that it’s primarily the postmenopausal patients. This study took young and older women. It was just a big mishmash of everyone with breast cancer.
Hope S. Rugo, MD: It’s interesting that the ABCSG trial looked at these 2 bone-remodeling agents. Where they showed a benefit was in patients who were receiving endocrine therapy and no chemotherapy. I think that’s an important aspect of these trials. It’s possible that chemotherapy affects the ovarian function, and you know you’ve got the endocrine therapy part of it, and all sorts of different aspects in a higher-risk population. Certainly, in the D-CARE trial, that was the case. So, it is still difficult understanding exactly who benefits, even with zoledronic acid, with these bone-active drugs. But clearly somebody does, in terms of bone metastases.
Joyce A. O’Shaughnessy, MD: Denosumab is indicated for AI-treated postmenopausal women who are osteopenic or osteoporotic. We can reliably go with that in our practice. Of course, we also have zoledronic acid every 6 months in the NCCN guidelines for patients.
Hope S. Rugo, MD: I have to say, denosumab is not approved in that setting.
Sara A. Hurvitz, MD: Right.
Hope S. Rugo, MD: Certainly not in California. It’s more expensive. Most insurers want you to give zoledronate. But we can be happy giving zoledronic acid in that setting.
Joyce A. O’Shaughnessy, MD: For our postmenopausal women, we should be using one of the bone agents in their care. I agree. That’s probably the best hypothesis. The patient populations were just so different in the 2 trials. The ABCSG-18 trial was much more narrowly focused on the homogenous population of postmenopausal endocrine therapy—treated patients and looked quite good.
Debu Tripathy, MD: I think there are intrinsic differences in these 2 cancer types that were represented in this study. If you look at hormone receptor—positive disease, the CTCs are predictive of outcome. The bone seems to be an important microenvironmental factor and may even be a reservoir for micrometastases. Anyway, that’s just a hypothesis. I think there are so many differences between the trials that it’s hard to sort that out.
Joyce A. O’Shaughnessy, MD: Yes.
Transcript Edited for Clarity