Denosumab Reduces Fractures by 50% in Postmenopausal Women

Adam M. Brufsky, MD, PhD

Certain bone-targeted agents deserve more frequent use in oncology, although providers need to be mindful about patient conditions and the potential for osteonecrosis, said Adam M. Brufsky, MD, PhD, who will provide an update on bone-targeted agents during Friday's Medical Track at the Miami Breast Cancer Conference.

Brufsky said denosumab (Xgeva), showed a disease-free survival benefit in postmenopausal women with early hormone receptor-positive breast cancer in the Austrian Breast and Colorectal Cancer Study Group-18 (ABCSG-18) trial. Denosumab was given to women who had received aromatase inhibitor (AI) therapy. From 2006 to 2013, the trial enrolled 3425 patients, of whom 3420 were randomly assigned to receive denosumab 60 mg (n = 1711) or placebo (n = 1709) subcutaneously every 6 months. Denosumab reduced the rate of fracture in women by almost 50%, from 176 to 92 (HR, 0.50; P <.0001), compared with placebo.

Given the damage that adjuvant endocrine therapy can do to bone health in breast cancer patients, these findings may change clinical practice, said Brufsky, associate chief of the Division of Hematology/Oncology and co-director of the Comprehensive Breast Care Center, University of Pittsburgh.

The follow-up analysis of the benefits of adding denosumab to AI therapy showed that denosumab also reduces the risk of breast cancer recurrence and death in post-menopausal women.

In his preconference interview withTargeted Oncology, Brufsky discussed considerations for using denosumab as well as zoledronic acid (Zometa) as in patients with breast cancer.

TARGETED ONCOLOGY:What is new in bone-targeted therapies?

Brufsky:

Based on meta-analysis studies, there are a number of bone-targeted agents in the postmenopausal setting that have demonstrated a 3% improvement in overall survival in patients with breast cancer at 10 years. The real question is, why do we not use them? There are clearly good data available and the questions revolve around which one do we use, how frequently we use it, and for how long. In my opinion, anywhere from 2 to 5 years in the meta-analysis seems to be the right amount.

There are some randomized trials that seem to provide a disease-free survival benefit such as with denosumab, which is a little bit different than the bisphosphonates. The ABCSG-18 trial gave us a very nice result that we need to talk about as a group of breast cancer physicians. Hopefully, we&rsquo;ll come to some sort of consensus as to how these drugs should be used.

TARGETED ONCOLOGY:What is the current standard of care for patients with bone metastases?

Brufsky:

When managing the patient with bone metastases, there are a number of therapies to consider. If the patient is ER-positive, consider using estrogen-receptor therapy. If the patient is triple-negative, oncologists will most likely treat with chemotherapy. If the patient is HER2-positive, consider using a combination of trastuzumab (Herceptin) plus pertuzamab (Perjeta). But more important, oncologists should be using a bone-targeted agent, either denosumab or zoledronic acid.

An interesting trial (NCT00869206) that has come up recently and was just published, was a randomized trial performed by the Cancer and Leukemia Group

B cooperative trial group. It concluded that giving zoledronic acid every 3 months was equivalent to giving it monthly for the management of metastatic bone disease. In fact, the interesting thing is that, in this trial, the event rate that was observed—bone-related complications like a fracture, or a pain, or need for radiation of bone&mdash;was equivalent in the less-frequent dose compared with the monthly dose.

That is a big deal, because now patients only have to receive the medication every 3 months and not monthly. This is helpful for the patient; however, when a woman has metastatic breast cancer, there are a lot of things you find in a monthly visit that you may not see in the 3-month visit. I think the potential loss of that monthly screening is something we need to consider because there are things that a patient can develop that can be prevented before they get worse.

For example, a patient could develop the beginning of a spinal cord compression or start to have a little bit of weakness in her legs. The oncologist can pick that

up on a monthly visit and may miss it on a visit every 3 months. I think we are going to be moving to visits every 3 months, and it will be positive in some instances that women only have to receive treatment every 3 months. It is less costly, and probably less toxic, but the concern the oncologist has is with patient management.

TARGETED ONCOLOGY:What are the adverse events for these bone-targeted agents?

Brufsky:

There are not a lot of adverse events, but I think the biggest one is renal insufficiency, which can occur if you give the drug too fast. A certain proportion of women with zoledronic acid can get achiness and febrile syndromes that last up to 1 week or even 2 weeks. That is uncommon but it can happen.

The big one for both denosumab or zoledronic acid, is that a certain percentage of women, probably 1% or 1.5%, will develop osteonecrosis of the jaw. What this means is that they will develop an exposed bone that can erode, especially if the patient has had an implant or some sort of invasive dental procedure that does not heal, and this can be prevented by cognizance. Having a woman tell us that she is getting a dental procedure can help physicians adjust to whether they should give the drug or not.

My own bias is that this is somewhat of a peak effect. In other words, getting a dental procedure a day or 2 after getting the bisphosphonate is not going to be wise. Usually, it will delay the administration of a bisphosphonate 1 to 2 months due to the dental work.

What does the future hold for bone-targeted agents? In my opinion, the big thing is the adjuvant therapy, especially if we are moving toward finding a group of patients who are not going to need chemotherapy, and we do not know that now. With all the new genomic testing that is coming out—whether it is the 70-gene assay, the 21-gene assay, or the PAM50&mdash;all of these tests are telling us that there is a subset of patients who do not need chemotherapy. The issue is that you have patients whom physicians are just going to treat with hormone therapy, but they could possibly still have a lot of nodes or have a high risk of recurrence, even if treated with endocrine therapy.

What should we do for those women? I suggest that, especially in the postmenopausal setting, bisphosphonates may give you a benefit if you are not going to give chemotherapy.

References:

1. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant deno- sumab in breast cancer (ABCSG-18): a multicenter, randomized, double-blind placebo-controlled trial. Lan- cet. 2015;386(9992):433-443. doi: 10.1016/S0140- 6736(15)60995-3.