AT THE 2015 ASCO ANNUAL MEETING

CHICAGO (FRONTLINE MEDICAL NEWS)Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.

Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.

“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.

“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”

“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”

Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.

Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.

In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.

The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.

At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.

The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.

Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.

The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.

Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.

tor@frontlinemedcom.com

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