Letrozole Study's Early Stop Pleased—But Didn't Surprise—Researchers

TORONTO—Researchers studying the aromatase inhibitor letrozole were pleased ad excited—but not entirely surprised—when the Canadian-led international study was stopped early. “In my heart of hearts, I was not surprised,” said principal investigator Paul E. Goss, MD, PhD, of Princess Margaret Hospital here. “We knew the number of events was lower than we had anticipated,” Dr. Goss said in an interview, “and I said, jokingly, that perhaps it was because the drug was working so well we were not seeing recurrences.” It was no joke: The study was stopped at its first planned interim analysis because the independent data monitoring committee felt it would no longer be ethical to withhold letrozole from women in the placebo arm of the study. The rate of recurrence in women taking the drug was significantly lower—43%—than the rate in women taking placebo, Dr. Goss told a news conference here. “Because of the efficacy, we were obliged to stop the trial,” he said. Study Specs The study enrolled 5,187 postmenopausal women who were disease-free and who had completed five years of tamoxifen—a population for which there had been no approved continuing treatment. Roughly half of the nearly 250,000 women diagnosed with breast cancer every year in North America fit into that group and could benefit from letrozole, the researchers estimated. “It's a large number of women,” said the study's US coordinator, James N. Ingle, MD, of the Mayo Clinic. Also at the news conference, cancer survivor Kathy Anderson said the lack of treatment was a “dark cloud” hanging over women who are coming to the end of their tamoxifen therapy. “This study offers hope to women,” she said.Figure‘Lighter Step, Excited, Pleased, Cheering’ After 20 years in clinical practice, Dr. Goss said, “I'm going to the clinic tomorrow with a lighter step.” “When something works, it's exciting,” Dr. Ingle said, “so I would say we were excited, we were pleased.” But, he added, “it's very unusual to have such a dramatic effect” that the study is halted prematurely, and the sudden stop means that some questions—such as the optimum length of letrozole therapy—remain unclear. Another of the study's leaders, Kathleen I. Pritchard, MD, said she learned of the decision when she was given an hour's notice for an emergency conference call late in August. “As soon as I got the phone call [asking her to be ready for the conference call], I knew what it was,” said Dr. Pritchard, of the Toronto-Sunnybrook Regional Cancer Centre. “I think we were surprised that we saw this result so soon.” Ordinarily, planned interim analyses pass without much notice; the last major study stopped early, Dr. Pritchard said, was the pivotal P-1 study that established tamoxifen as the standard of care for women with early breast cancer. “Everybody was cheering,” when the results of that study were communicated to the investigators, said D. Lawrence Wickerham, MD, Associate Chairman of the National Surgical Adjuvant Bowel and Breast Project (NSABP), which ran the P-1 trial. The enthusiasm was high, said Dr. Wickerham, who was protocol officer on the P-1 study, because it established for the first time that chemoprevention of breast cancer was possible. The letrozole study builds on that fact, he said. “This is certainly good news for women with hormone-responsive breast cancer. It gives them another option at the end of tamoxifen therapy.” ‘Sufficiently Striking’ And, he added, the results are sufficiently striking that there should be “enthusiasm” for testing the drug earlier, as is being done with the aromatase inhibitor anastrozole, now being tested head-to-head with tamoxifen. When the letrozole study was stopped, there had been 207 local or metastatic recurrences of breast cancer or new primary cancers in the other breast—75 in the letrozole arm and 132 in the placebo arm. Based on those numbers, the researchers estimated four-year disease-free survival rates of 93% for letrozole and 87% for placebo—highly statistically significant at the p<0.001 level. Putting the numbers another way, the researchers estimated that treating 16 women for four years would prevent one “event”—a recurrence or new primary cancer in the other breast. Overall survival—not a stated goal of the study—also favored the letrozole arm, but didn't reach statistical significance, Dr. Goss said. Osteoporosis Because aromatase inhibitors block estrogen production, they are associated with an increased risk of fractures, but Dr. Goss said there was no difference in clinical fracture rates between the two arms. There were, however, more diagnoses of osteoporosis in the letrozole arm (5.8% vs 4.5%), but Dr. Goss said that was based on self-reporting of an outside diagnosis and was not reflected in actual broken bones. A bone substudy is still under way—in fact, Dr. Goss said, there will probably be several more publications as the researchers complete analyzing the findings of the main study. Immediate Reaction Reaction to the news among cancer survivors and patients was immediate—phone lines lit up at both the Canadian Cancer Society and the American Cancer Society. “Our call volume to our cancer hot line is up by about 40% already, and I suspect the calls will continue as the news spreads,” Anne Vézina, a spokesman for the Canadian Cancer Society, told reporters the day after the Toronto news conference. A spokesman for the American Cancer Society said there were about 400 calls seeking information about the study the day after the news conference, although the number is dwarfed by the million or so calls the society's hotline gets every year. Cost Not counting drug costs, the study cost more than $20 million (Canadian dollars) said Lois Shepherd, MD, Trials Coordinator for the National Cancer Institute of Canada Clinical Trial Group in Kingston, Ont., east of Toronto. The Canadian clinical trials group initiated the study, after a proposal from Dr. Goss. Of the $20 million, the US National Cancer Institute kicked in about $8 million, and Novartis AG—the makers of letrozole—put in about $12 million, as well as supplying drugs for the study. The Canadian Cancer Institute supplied core financing for the operations of the Kingston clinical trials office. The study raises an immediate question: Letrozole is approved in Canada and the United States only for advanced breast cancer in postmenopausal women and, while off-label use is possible, it's not clear how the drug would be paid for in that case. “It's an expensive drug,” selling for about $6 a pill in the US, Dr. Ingle said. Since it must be taken daily, that adds up to about $2,100 (US) a year. He added that the study is probably strong enough that regulatory agencies would consider allowing it as support for a new indication for letrozole.

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