SAN ANTONIO — Arzoxifene, a once-promising selective estrogen-receptor modulator, experienced a fatal meltdown in a phase III trial involving nearly 10,000 women.
Arzoxifene was being developed for prevention of both fractures and breast cancer in postmenopausal women with osteoporosis or osteopenia.
But the 9,354-patient randomized, double-blind, placebo-controlled, multinational GENERATIONS trial has put an end to that, Dr. Trevor Powles said at the San Antonio Breast Cancer Symposium.
The breast cancer prevention portion of GENERATIONS went well: After 48 months of follow-up, arzoxifene reduced the incidence of invasive breast cancer by 56%, compared with placebo, and reduced estrogen-receptor–positive invasive breast cancer by 70% (see chart).
Arzoxifene also significantly reduced the incidence of vertebral fractures by 41% after 36 months of follow-up in GENERATIONS participants, who were aged 60-85 years at enrollment.
But there was a deal breaker: the selective estrogen-receptor modulator (SERM) produced no significant reduction in nonvertebral fractures.
“This is disappointing because as an antiosteoporosis drug we really need to have a SERM that would not only reduce vertebral fractures, but nonvertebral fractures as well,” explained Dr. Powles, a medical oncologist who is professor emeritus at the Institute of Cancer Research, London.
Moreover, arzoxifene was associated with increased rates of venous thromboembolism, endometrial polyps, leg cramps, hot flashes, and cholelithiasis, while offering no better protection against cardiovascular events than did placebo.
“The overall benefit/risk profile of arzoxifene does not represent a meaningful advancement in the treatment of osteoporosis, so further development of this drug will not take place. It's obviously disappointing, given that so much time and effort has been put into a major trial with good preclinical and early clinical data,” he said.
The investigators are still puzzling over how the earlier studies could have been so misleading.
Arzoxifene is a benzothiophene SERM, like raloxifene, which is approved in postmenopausal women for the treatment and prevention of osteoporosis as well as for invasive breast cancer risk reduction in such women who are at high risk for the cancer or who have osteoporosis.
In early clinical studies, arzoxifene had greater effects on bone mineral density and bone turnover markers than did raloxifene.
Moreover, in the GENERATIONS trial arzoxifene resulted in increased bone density at nonvertebral sites as well as in the spine.
GENERATIONS was funded by Eli Lilly & Co.
Dr. Powles disclosed that he has no relevant financial relationships.
It's disappointing, given the time and effort 'put into a major trial with good preclinical and early clinical data.'
Source DR. POWLES
Elsevier Global Medical News