December 22, 2014

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume 1, Winter 2005

SURROGATE MARKERS
Saving Years in the Race to Test New Drugs

Good news for men with a rising PSA after treatment for prostate cancer: Fresh insight into how PSA behaves, gleaned at the Brady, may shorten the drug development pipeline by years—which means men will have access to new and possibly better drugs sooner than ever before.

Until now, it has been difficult to study chemotherapy in men with prostate cancer because the Food and Drug Administration (FDA) has historically required that the drugs show a “survival advantage.” This stipulation, although well-meaning, has been hard on everybody—on patients, of course, but also on drug companies, because this proof can take up to 15 years.

The irony—for men with metastatic prostate cancer, who need better medicine to contain it, and for the scientists who are trying to get it to them—is that the drug companies are discovering new drugs “at an alarming rate,” says urologist Alan W. Partin, M.D., Ph.D., Bernard L. Schwartz Distinguished Professor of Urology. But “very few of the drugs that demonstrate activity against the disease in laboratory testing ever make it to widespread use by patients, due to lack of clinical trials.”

What can PSA dynamics tell us?

There has got to be a better way, and Partin and colleagues believe the key may lie in following the dynamics of PSA—whether it comes back at all after treatment, when it comes back, and how long it takes for the PSA levels to double. They have tracked the course of PSA in nearly 5000 men who underwent radical prostatectomy at the Brady since 1982. Their work, which Partin presented at the recent meeting of the American Urological Association, has produced enough reliably predictive data to demonstrate that PSA can serve as a surrogate marker of survival for these patients. These findings are so impressive that the Food and Drug Administration (FDA) is considering using them, along with data from other institutions, in clinical trials as surrogate markers of survival for the men who might benefit most from novel forms of chemotherapy.

So far, the FDA has considered PSA changes too murky an endpoint for any prostate cancer study, because there was no way to tell which men with an elevated PSA after treatment are at high risk of dying, and which men will live for years before the cancer progresses.

Partin and colleagues believe the key may lie in following the dynamics of PSA—whether it comes back at all after treatment, when it comes back, and how long it takes for the PSA levels to double.

As a result, treatment groups are filled with “apples and oranges,” says Patrick C. Walsh, M.D., “and it takes too long, for too many patients entered into a study, before a result can be determined.”

Partin and colleagues have found a way to separate men with a rising PSA after treatment into high-risk and low-risk groups. The high-risk patients tend to be a more homogenous group, with a faster-moving form of cancer—information that can now permit studies of drug efficacy to be carried out on smaller numbers of men in a shorter period of time.

The records of these patients are, in effect, a series of snapshots of cancer. Partin has found two that are the most critical. The first freeze-frame is the point of a man’s first rise in PSA after surgery. In this study, 19 percent of the men had an elevated PSA after radical prostatectomy; on average, the PSA began to go up 8.4 years after surgery. The next freezeframe is the point at which that number doubled.

The irony: Scientists and drug companies are discovering new drugs “at an alarming rate.” But very few “ever make it to widespread use by patients, due to lack of clinical trials.”

Partin found that men with the most rapid doubling time—for example, a man whose PSA level goes from 1 to 2 in less than 10 months—had the greatest chance of eventually developing metastatic disease and dying from cancer. Five years after that first PSA rise, 90 percent of the men were alive. Ten years after that first elevation—which means, on average, 18 years after their radical prostatectomy— 50 percent of those men had died.To put it into perspective, of these 5,000 men, only a small percentage—2.4 percent— died of prostate cancer. But by using Partin’s snapshots, and identifying the men who have a rapid PSA doubling time (of less than 10 months), Partin says, “we can identify men who might benefit from aggressive therapy earlier.”

 

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