ODAC Recommends Approval of Aredia for Breast Cancer Bone Mets

July 1, 1996

GAITHERSBURG, Md--The FDA's Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend approval of Ciba-Geigy Corp.'s Aredia (pamidronate disodium for injection) for the treatment of osteolytic bone metastases in breast cancer patients undergoing either chemotherapy or hormonal therapy.

GAITHERSBURG, Md--The FDA's Oncologic Drugs Advisory Committee(ODAC) voted unanimously to recommend approval of Ciba-Geigy Corp.'sAredia (pamidronate disodium for injection) for the treatmentof osteolytic bone metastases in breast cancer patients undergoingeither chemotherapy or hormonal therapy.

The panel recommended approving the drug for hormonal therapypatients despite the concerns of some members that the supportingdata appeared weak. The panel declined to recommend that FDA approveAredia for use in bone metastases from other types of tumors.

Aredia, a bisphosphonate, is a new class of osteoclast inhibitorthat retards the resorption of bone. Ciba-Geigy officials andtheir outside consultants discussed two placebo-controlled, double-blinded,randomized trials in breast cancer patients who had developedlytic bone lesions.

One, P19, involved 382 patients receiving chemotherapy; the second,P18, studied 371 patients receiving hormonal treatments. Bothtrials used "skeletal related events [SREs] excluding hypercalcemia"as their primary endpoint. These included pathological fractures,spinal cord compression, radiation for pain, and surgery to bone,said John Seaman, PharmD, of Ciba-Geigy.

In P19, women getting Aredia in addition to chemotherapy had amedian time to their first SRE of 13 months, compared with 7 monthsfor the women in the chemotherapy-placebo group. The Aredia-treatedwomen also suffered fewer SREs, a mean of 2.1 per year, comparedwith 3.3 for the placebo group.

Trial P18 showed that women receiving hormonal therapy plus Arediahad a median time to first SRE of 10.9 months, compared with 7.4months for the placebo group. The Aredia group experienced a meanof 2.4 SREs per year vs an annual mean of 3.5 SREs in the placebowomen.

In his efficacy and safety analysis, Dr. Seaman also presenteddata from P12, an Aredia trial in 392 multiple myeloma patients.Among the P19 and P12 patients, he said, "after 9 to 21 monthsof monthly therapy, the proportion of patients having SREs wassignificantly less on Aredia than on placebo."

The number of deaths in the three studies were similar betweenthe Aredia and placebo groups--125 (23%) vs 141 (24%), respectively--andnone were attributed to the study drug, Dr. Seaman said. However,neither breast cancer study showed any difference in survivalbetween the Aredia and placebo groups.

One Aredia-treated patient each in P18 and P19, and seven myelomapatients getting the drug in P12, had "potentially seriousand unexpected side effects," Dr. Seaman said. Less threateningside effects, experienced by at least 15% of both Aredia and placebopatients in the breast cancer trials, included skeletal pain,fever, and myalgia. The reactions were less common in the Arediapatients.

In addition, Dr. Seaman noted, an acute phase reaction usuallyfollows the injection of Aredia. This includes bone pain, arthralgias,myalgias, and fever, and lasts for 24 to 48 hours.

The panel agreed unanimously that trial P19 demonstrated Aredia'ssafety and efficacy in chemotherapy patients. But for P18, thepanel split 3-to-3 with one abstention. Some panel members feltthat the statistical significance between Aredia and placebo patientsin P18 wasn't powerful enough to clearly demonstrate efficacy.Nonetheless, the committee voted unanimously to recommend thatthe FDA approve Aredia's use with both chemotherapy and hormonaltherapy.

If the FDA approves Aredia for breast cancer patients, ODAC ChairmanPaul Bunn, MD, of the University of Colorado, urged that the packagelabeling state that the beneficial effect "didn't seem tobe as great in the hormonal patients."