Dendreon Clinical Trial Primer: What You Need to Know About Today’s Provenge Data

4/28/09Follow @xconomy

Dendreon said it made history a couple weeks ago, when its drug for stimulating the immune system to fight cancer cells was found to be the first of its kind to help men with prostate cancer live longer. Today, we’ll find out just how strong the medical evidence is to support that claim.

The Seattle biotech company (NASDAQ: DNDN) plans to release detailed results on its experimental drug, sipuleucel-T, (Provenge) from a clinical trial of 512 men with terminal prostate cancer. Data from the trial, called IMPACT, will be presented at the American Urological Association in Chicago at 2:20 pm Central time//12:20 pm Pacific.

Dendreon, of course, has already seen the data, but researchers, investors, and patient advocates haven’t. All we outsiders know is that the company’s CEO, Mitchell Gold, has characterized the data as “consistent” with results from prior clinical trials, and that there was no gray zone for interpretation. He called the findings “unambiguous” and a “clear hit.”

If doctors interpret the data the same way, this would be a big step forward for prostate cancer treatment. About 30,000 men in the U.S. die each year of the disease, and given the high price something like Provenge is bound to command, analysts predict this drug could exceed $1 billion in annual sales. Dendreon is so pumped about this result that it hung a banner on its building in Seattle’s Belltown neighborhood that looks to be 30 feet tall by at least 40 feet wide after it announced success on April 14. It says “Congratulations Dendreon. Global Impact Starts Here,” with a blue ribbon for prostate cancer patients.

Before we get too far ahead of ourselves in counting up the dollars and the Nobel Prizes, I figured many readers could use a reminder of what is in the public domain about Provenge and what to watch for in the data.

The biggest trial to support the effect of Provenge to date is called 9901. That study, of 127 men, produced results in 2005. It showed that men with terminal prostate cancer lived a median time of 25.9 months if they were randomly assigned to get Provenge, compared with a median of 21.4 months if they got a placebo. Median means that half lived less that than amount of time, and half lived longer. (Statisticians prefer to use medians because averages can be warped by individual outliers who might die immediately or live 10 years for some other reason).

The findings from this study meant that men lived a median time of 4.5 months longer, or 21 percent longer, if they got Provenge. This result was highly statistically significant, with a p-value of 0.01. That meant there was about a one in 100 possibility that the finding was due to chance, and not necessarily the drug, which is good enough to provide confidence to even the most conservative biostatisticians.

After three years of follow-up, the drug appeared to be looking even better. About one out of every three Provenge patients were still alive then (34 percent), compared with one out of 10 in the placebo group (11 percent). Dendreon has hypothesized that the drug appears to look better over time because it has a “delayed effect” as it takes time to rev up the immune system against prostate cancer.

These findings were not from the primary goal of the study, which prompts some statisticians to dismiss them out of hand. And another identical study in 98 patients, called 9902a, failed to produce evidence that was statistically significant, meaning it’s possible the first study could have been a fluke.

Still, when those two trials are pooled, as they were originally designed to be, the findings again favored Provenge. The median survival benefit in a total of 225 patients was still 4.3 months, with a statistical p-value of 0.0006. (That means it’s extremely unlikely that the survival benefit seen was due to chance, or that if Dendreon ran the trial 1000 times, they’d still expect to see a survival benefit each time.)

Since we’re talking about Dendreon, there is likely to be some drama and debate about this data. The latest trial, called Impact, started in 2003 and took six years to produce final enroll all the patients and follow them for the survival result. That’s a lot of time to enroll patients and follow them, and Dendreon will surely have to scrub through each individual patient record to make sure meticuluous records were kept to satisfy the FDA.

The trial also was modified half-way through, in 2005, to alter eligibility criteria for who could get in the study. Early on, the trial had been restricted to patients with less-aggressive tumor types, as ranked by Gleason scores, because at the time, Dendreon thought Provenge had a better chance of working for those patients. When later data suggested the benefit was more widespread across patient populations, it asked the FDA to amend the study to allow all comers into the trial, including those with tumor types that had spread and who had relapsed after prior hormone-deprivation therapies.

Dendreon, of course, tried and failed to win FDA approval in 2007 based on the earlier set of data, which is a long story that I wrote about on April 3. But once it became clear it needed to produce good results from Impact to get approval, Dendreon had an idea for how to speed up results.

Because Dendreon was eager to turn it its application to the FDA, it negotiated for the right to take an early peek at the data from the Impact study in the fall of 2008, a practice known as an interim analysis. This meant that if the drug was obviously showing a survival benefit as data started trickling in, Dendreon could whip up a faster application to the FDA and bring it to the market sooner. It also meant that it would introduce some bias into the study, and that FDA statisticians would insist on Dendreon clearing a higher statistical bar than usual when the final analysis comes in. The FDA standard for statistical significance is when a trial has a p-value of 0.05 or less, with the smaller number being the better number. Dendreon has not disclosed how much of a p-value penalty it paid for taking that early peek, but it’s safe to say it will need to show a p-value of something a fair bit lower than 0.05 to win over its skeptics.

The Impact trial was designed to primarily measure survival time in men whose prostate cancer had spread and resisted prior therapies. It was meant to succeed if it were consistent with the earlier results, showing a 22 percent reduced chance of death during the study, known in biostats parlance as a hazard ratio. The side effects from earlier studies were mild fever and chills that typically lasted a couple of days after Provenge injections. This is the advantage many patients are excited about, because hormone deprivation amounts to chemical castration, and chemotherapy is also known for its rough side effects.

Dendreon didn’t compare Provenge head-to-head in this clinical trial against the standard of care for this terminal form of prostate cancer, docetaxel (Taxotere) from Sanofi-Aventis. This competing drug produced a median survival of 19.3 months in its pivotal clinical trial, called TAX-327, which was about a 3-month advantage compared with a placebo. About one-third of patients suffered serious side effects.

Although it’s always dangerous to compare one clinical trial to the next, people always do anyway, and Provenge’s Impact data is likely to stack up well side-by-side, says David Miller, CEO of Seattle-based Biotech Stock Research. He has developed a “cheat sheet” to compare the most important data points from the trials side by side.

The Impact study is likely to show it is somewhat better than Taxotere, although probably something short of the results seen in the earlier Provenge trial called 9901, Miller said in a note to clients on April 26. “As long as that is true, we expect little long-term drama even though the price will vary wildly depending on where the Impact data falls in this bracket,” Miller wrote.

Dendreon continued to surge in trading yesterday, climbing $1.47 to close at $21.55 at the close on more than triple the average trading volume. Today could be an even bumpier ride depending on what the company says to an audience of physicians at the McCormick Place convention center in Chicago.

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