As people age, the risk of fracturing a bone – whether it’s a hip, a wrist, vertebrae, an ankle or toe, climbs steadily. For women and men who live after a cancer diagnosis, the risk of breaking bone is greater.
At this year’s San Antonio Breast Cancer Symposium, Dr. Michael Gnant of Vienna gave an update on a major trial of denosumab in its capacity to reduce fractures and possibly stave off metastases. This drug is manufactured and sold by Amgen in a low-dose form as Prolia. Prolia is a monoclonal antibody that doesn’t require intravenous administration; it’s injected under the skin, just twice each year.
The ongoing trial, by the Austrian Breast and Colorectal Cancer Study Group (ABCSG), includes over 3,400 postmenopausal women with non-metastatic, hormone receptor positive breast cancer. All participants took an aromatase inhibitor, a standard treatment given to lower hormone levels, and were randomized to receive either low-dose (60 milligrams) denosumab or a placebo injection under the skin, twice yearly.
Recently the ABCSG group published the clear finding from this same study that Prolia halves the risk of bone fractures in postmenopausal women who take aromatase inhibitors for non-metastatic breast cancer.
Now it appears that Prolia also reduces breast cancer recurrence. Based on updated data from the ABCSG-18 trial, disease-free survival is prolonged, slightly, in women assigned to receive denosumab, as compared to those on placebo. With a median follow-up of 4 years, the odds of recurrence were reduced by 18% in women taking Prolia. This advantage approaches statistical significance, now nine years after the study began, with a clear trend and greater difference observed among women who had larger tumors.
The benefits of Prolia in this setting – for postmenopausal women with hormone-sensitive, non-metastatic breast cancer – appear to exceed those reported for a competing class of drugs, bisphosphonates. A recent analysis of studies of bisphosphonates – agents like Actonel, Boniva, Reclast and others – suggests that the survival benefit is close to nil, and that the reduction of fractures is not as great as that observed with Prolia.
What’s more, Prolia is a well-tolerated drug. In an interview, Gnant told me this: “This was a double-blind, placebo-controlled trial. Often in these kinds of clinical trials, doctors can tell who’s getting the drug, based on side effects. With this drug, we couldn’t tell.” The investigators couldn’t discern any difference in adverse events between the two groups, denosumab or placebo. “There were rare adverse events, of course, but those were typical effects of aromatase inhibitors, and might be attributed to those”
At the press conference about the findings, a co-panelist asked Gnant about denosumab, and how it compares to bisphosphonates. “It’s a very safe treatment,” he stated. “If my mother were affected, I would give it to her tomorrow.”
He summarized the study findings: Prolia cuts the incidence of bone fractures by half, and has, if anything, a positive effect on reducing breast cancer recurrences. He said that the differences in results between the study arms were so great, in terms of reducing fractures, that an independent data monitoring committee has requested the trial be un-blinded: In 2016 all women in the study will have the opportunity to find out what they’ve been taking, and can choose to take Prolia if they’ve been getting the placebo.
The denosumab study is supported by
The population of breast cancer survivors who are postmenopausal and at high risk for fracture is huge. Overall, two thirds of cases are detected in women over age 55 years. Given the rates of breast cancer, with hundreds of thousands of new cases each year, and the aging population, the use – and potential benefit – of drugs like denosumab is large and will grow.
For postmenopausal women who take aromatase inhibitors for estrogen-sensitive breast cancer, the normal decline in bone strength is exacerbated by hormone-blocking drugs, significantly augmenting the fracture risk. The same goes for men with prostate cancer, if they receive androgen-blocking treatments.
Patients tolerate Prolia well, confirmed Dr. Linda Russell in a phone interview. She’s a rheumatologist at New York’s Hospital for Special Surgery who specializes in osteoporosis and bone health.
“With oral bisphosphonates, some people do have symptoms like heartburn,” she said. With infusions of bisphosphonates, patients sometimes get flu-like symptoms,” she considered. “You really don’t see that with Prolia.”
There’s probably more literature supporting the use of bisphosphonates than for the antibody, she considered. “But that might be simply because those are older drugs.”
I asked Russell if she’s prescribed Prolia for men at high fracture risk, or with a history of prostate cancer. “There’s no reason why I wouldn’t,” she responded.
Denosumab is a monoclonal antibody that binds a protein, RANK Ligand (RankL), an inflammatory molecule that controls bone growth and remodeling, changes that occur in response to normal aging and stress. Although many aspects of how RankL, and the antibody work remain uncertain, the drug is thought to possibly inhibit bone metastases by silencing the marrow. With RankL blocked, and less bone turnover, dormant tumor cells might remain quiet, Gnant suggested.
Amgen manufactures two versions of this drug, with distinct names: Prolia and Xgeva. The doses, indications and potential toxicity, differ quite a bit.
In 2010, the FDA approved Prolia for post-menopausal women with osteoporosis and increased risk for bone fractures. In 2011, it was approved for treatment of men with non-metastatic prostate cancer who receive androgen deprivation therapy (ADT), and for women who take an aromatase inhibitor (AI) for adjuvant treatment of (non-metastatic) breast cancer. This drug has also been approved for use in men with osteoporosis at high risk for bone fractures.
In what might be a distraction, the actress Blythe Danner, talks about Prolia on Amgen’s website, here.
Xgeva is a higher-dose preparation of denosumab that the FDA has approved for use in patients with metastatic solid tumors (like breast and prostate cancer) with bone disease. It is also prescribed for patients with multiple myeloma, to reduce bone disease including fractures. This drug is typically given by injection every four weeks, and carries a higher risk of adverse reactions.
The CDC reports that over 250,000 people, age 65 and older, are hospitalized each year in the United States for hip fractures. And that’s just hips: If you consider the costs of surgery and debility from all kinds of bone breaks, and how painful those can be, it’s devastating.
Prolia is not a particularly expensive medication. It appears to be well-tolerated at this dose, and has been well-studied. Apart from the ABCSG trial, a UK-based D-CARE study has pending results. So far, it appears to be very effective in preventing factures, and may help lessen the odds of metastatic disease after cancer treatment with hormone-blocking therapy.
Perhaps doctors and patients should be considering denosumab more often, at an alternative to bisphosphonates, which are commonly prescribed for the same or similar reasons and, for many patients, less easy to take.
