Should The J&J Zytiga Trial Have Ended Early?

Two months ago, a late-stage trial found that Zytiga, a Johnson & Johnson treatment for prostate cancer, improved survival in patients who had not received chemo – the pill delayed cancer growth and helped patients live longer versus a placebo. And so, an independent data monitoring committee to recommend that patients who are on placebo should be given Zytiga, which was approved last year to treat advanced prostate cancer in patients who did not benefit from chemo.

Only interim results were released, but the outcome was being closely watched for several reasons, and high on the list was the affect on competitors, such as Dendreon and its rival Provenge treatment. Although cost comparisons have been a perennial point of discussion when evaluating the two medications, a key issue is when physicians may decide to migrate their patients to Zytiga. And the study data suggested to some that the scales would tip in favor of Zytiga.

Yet, J&J did not immediately disclose that Zytiga did not show a statistically significant oversall survival benefit; J&J only acknowledged this point when asked. The findings raised questions about the decision by the data monitoring committee to unblind the study of 1,088 patients, which was called COU-AA-302. And at the time, there was also speculation the move may have reflected concern over the timing of the Zytiga patent expiration.

Over the weekend, the data was reviewed at the American Society of Clinical Oncology meeting and, based on 43 percent of events, or 333 deaths, the committee estimated Zytiga provided a 33 percent survival improvement, or about nine months compared with placebo. The nine-month benefit was better than expectations prior to the meeting, which pegged an improvement in survival at five to six months, compared with 4.1 months registered by Provenge, according to Deutsche Bank analyst Robyn Karnauskas.

This was “right at the threshold” of statistical significance and “a very strong trend favoring Zytiga,” she wrote in an investor note. The committee “was nearly 100 percent certain that Zytiga would eventually show a statistically significant benefit if (the) trial was allowed to proceed.” Meanwhile, other Wall Street analysts believe the results also foretell an upbeat prognosis for the J&J drug, which is already being used on an off-label basis – reportedly about 30 percent of current Zytiga usage – and this trend is now expected to continue.

“While the interim overall survival endpoint missed the prespecified significance level, we believe the significant benefit in radiographic progression-free survival and secondary endpoints are sufficient for approval and solid commercial adoption (even without overall survival in the label),” Wells Fargo analyst Larry Biegelsen writes in an investor note this morning. He estimates Zytiga sales will hit $1 billion this year, although he adds that grabbing the pre-chemo market will be more challenging with looming competiton from a similiar pill being developed by Medivation.

Meanwhile, Biegelsen sought to dispel speculation the trial was unblinded due to patent concerns. Zytiga, he writes, is protected by a new chemical entity patent that expires in 2016, “suggesting generic competition is unlikely, although not impossible, until 2017.” Any confusion may be traced to a composition of matter patent listed in the Orange Book, which he writes will expire in 2014. We asked J&J for clarification and will update you accordingly.

Meanwhile, Peter Droppert, a consultant, writes on that unblinding the study was the wrong choice. “The judgment of the DMC has to be questioned. The decision to unblind the study means that the ‘interim’ data… is effectively the final data for the randomized trial. Unblinding a study introduces biases, which essentially turns a well-controlled randomized study into an observational one… By halting the study early, patients in the placebo group are now being switched over to Zytiga, which makes the comparison between the drug group and the placebo group less clear.”

He maintains that it was worth waiting a little longer to determine whether overall survival could be statistically significant. He notes that Susan Halabi, an associate professor of biostatistics and bioinformatics at Duke University, yesterday explained the results by citing a graphic showing a curve in which Zytiga was very close to the boundary. “By halting the study early,” he writes, “patients in the placebo group are now being switched over to Zytiga, which makes the comparison between the drug group and the placebo group less clear.” Of course, this was the oh-so-threshold that prompted the DMC to decide the unblinding was warranted.

He then argues that some physicians will say it is unethical to continue giving some patients a placebo and he questions whether the FDA will accept the trial to assess approval for pre-chemo treatment. “There is a risk that they may not,” he writes, “as overall survival remains the gold standard that prostate cancer drugs are currently judged by.” Biegelsen disagrees and expects “100 percent probability” that the FDA will grant approval.

But Droppert attempts to make a wider point. “Statistical boundaries are set in order to guide decision making, and in the totality of the circumstances, there may be enough data to suggest that Zytiga is effective in the pre-chemo setting, but why not wait a few more months for more definitive evidence?… The study failed to show overall survival and no matter what the positive PR spin is put on the data, it is unlikely that the study will ever show statistically significant overall survival… On some level, this must be regarded as a failure of drug development. Ending studies in this way does a disservice both to medicine and the men who participated in the trial.”

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