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A decline of 30% or more in prostate-specific antigen level in the first 3 months after starting chemotherapy for hormone-refractory prostate cancer was found to have the highest degree of surrogacy for overall survival, based on results from a retrospective study.
Researchers evaluated a range of posttreatment declines in prostate-specific antigen (PSA), alterations in PSA kinetics, and pain response for surrogacy of overall survival associated with an every 3-week schedule of chemotherapy with docetaxel.
The investigators mined data from TAX (Taxotere) 327, an international phase III study in which 1,006 men were randomized to one of two treatment schedules of docetaxel, compared with mitoxantrone on a 3-week cycle.
TAX 327 was published concurrently with the results of the Southwest Oncology Group (SWOG) 9916 clinical trial comparing docetaxel and estramustine against mitoxantrone and prednisone in 770 men with advanced refractory prostate cancer (N. Engl. J. Med. 2004;351:1502-12).
Dr. Andrew J. Armstrong of Duke University, Durham, N.C., and his colleagues retrospectively analyzed the TAX 327 data to identify a reasonable end point for phase II clinical trials. Their finding confirmed a similar analysis of SWOG 9916 conducted by lead investigator Daniel P. Petrylak at Columbia-Presbyterian Medical Center in New York. However, the two analyses revealed a major difference in the proportion of treatment effect (PTE).
The PTE in the SWOG study was 1.0, or 100%, which suggested that a 30% or greater decline in PSA during the 3 months following initial treatment was a perfect surrogate. The TAX 327 PSA analysis produced a PTE of 66%, however, which was two-thirds of the survival benefit in this trial, and consistent with a moderate surrogate effect.
The divergent PTEs might be the result of estramustine use in the SWOG 9916 trial. Estramustine has hormonal activity that causes PSA to fall even further, thus allowing better discrimination of the two trial arms than was possible in the TAX 327 study.
"In view of our findings, we feel that overall survival should remain the primary end point for phase III studies at this time and for this disease state," he said, adding that surrogate values need to be considered in terms of their mechanism of action and must be validated before use in clinical decision making.
"In the past, people have used 50% declines in PSA response as recommended by the PSA Working Group of experts, but we're saying that you can probably use 30%, which is just as good if not better, in identifying active cytotoxic drugs," Dr. Armstrong said.
Other measures of PSA change or pain response had independent prognostic significance but did not achieve a higher degree of surrogacy than that demonstrated by 3-month PSA decline.
An important lesson from the TAX trial, according to Dr. Armstrong, is that although patients with rising PSA on chemotherapy probably are not benefiting from the regimen, that's no reason to stop treatment. "There are some patients whose PSAs rise and then go down in response to chemotherapy, so we recommend giving everyone at least 4 cycles of chemo and to ignore PSA during the first couple of months," he said, and added that the study showed a survival benefit with 10 cycles.
"If possible, we try to get patients through that number of cycles without giving up. And clinically, you can tell patients with a 30% PSA decline that they're likely to live longer. But don't give up."
In discussing the findings, Dr. Maha Hussain expressed concern about becoming "wedded" to PSA surrogacy.
"A surrogate needs to be validated within each class of drugs with a different mechanism of action," said Dr. Hussain, who is professor of medicine and urology at the University of Michigan, Ann Arbor, and a coauthor on the SWOG trial results.
"PSA and its derivatives are not acceptable as surrogate markers of clinical benefit at this time."
Armstrong A.J. Analysis of prostate-specific antigen decline as a surrogate for overall survival in metastatic hormone-refractory prostate cancer (HRPC). Abstract 5009.
Commentary |
Recent research has focused on identifying surrogate end points that could rapidly identify patients who will have good outcomes after chemotherapy. The study by my colleague Dr. Andrew Armstrong at Duke University and the Duke Prostate Center found that a greater than 30% decline in PSA within the 3 months after chemotherapy was a moderate surrogate for overall survival. Using data from the TAX 327 study, the researchers assessed various PSA declines for their ability to serve as surrogates of overall survival. TAX 327 was an international phase III trial in which 1,006 men randomized to 1 of 2 treatment schedules of docetaxel plus prednisone were compared with those given mitoxantrone plus prednisone every 3 weeks. The researchers found that a PSA decline greater than 30% was the best surrogate, though it explained just over 66% of the survival benefit from chemotherapy. This follows a finding by Dr. Daniel P. Petrylak and his colleagues from Columbia University that a PSA decline greater than 30% explained 100% of the survival benefit from docetaxel chemotherapy. The Columbia group used data from a large Southwest Oncology Group study of men with advanced hormone-refractory disease. Together, these reports suggest that a PSA decline greater than 30% is a reasonable surrogate of overall survival, though the search must continue for newer and better surrogates. Moreover, the FDA does not allow PSA changes to be included as end points in clinical trials for drugs, and the current data are unlikely to change the agency's position. — Stephen J. Freedland, M.D., and Judd W. Moul, M.D.
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