NEW YORK—Among prostate cancer patients with biochemical evidence of relapse after radical surgery, exisulind, a selective apoptotic antineoplastic drug, had a significant impact on rising PSA levels in a double-blind, placebo-controlled study, according to a report at the Chemotherapy Foundation Symposium XVIII.
"In the overall analysis, patients on exisulind experienced a significant suppression of rising PSA levels, compared to placebo, with the curve starting to separate at 2 months," said Diane Prager, MD, associate professor of medicine, Division of Hematology/Oncology, UCLA.
The drug, which is being developed by Cell Pathways under the trade name Prevatac, had a marked effect among the patients at highest risk of relapse.
The multicenter study enrolled 96 patients, 92 of whom were evaluable. To be eligible for the study, the post-prostatectomy patients were required to have a documented 10% PSA rise within the past 4 months, with levels of 0.4 to 15 ng/mL, but no evidence of metastatic disease. Prior hormonal therapy, except in the neoadjuvant setting, was not allowed.
Patients were categorized as being at high, intermediate, or low risk of developing metastatic disease, according to an algorithm developed by Pound et al (JAMA 281:1591-1597, 1999). The algorithm assigning patients to these risk groups took into account whether the first PSA rise occurred less than or more than 2 years after prostatectomy and whether PSA doubling time was longer or shorter than 10 months, as well as patients’ pathologic Gleason score. Multivariate analysis was then performed to provide a time-dependent risk of developing metastatic disease following PSA recurrence.
Among the study patients, risk was considered high for 14, intermediate for 35, and low for 33. A risk category could not be assigned to 11 patients.
Under the protocol of the 12-month study, the dose of exisulind was 250 mg twice daily. Of the evaluable patients, 45 received the oral agent and 47 placebo.
Study Results
The overall mean change from baseline PSA levels at 12 months was 1.07 ng/mL among patients receiving exisulind and 1.74 ng/mL in the placebo group, a difference that was statistically significant, Dr. Prager noted. The difference was even more pronounced in high-risk patients, 1.13 ng/mL vs 2.90 ng/mL.
The difference was also significant among the men who could not be classified into a risk group, and a trend toward significance was seen in the intermediate-risk group. "There was no significant difference in low-risk men, probably due to the small PSA change in both groups in this 12-month time period," she said.
PSA doubling times diverged significantly in the high-risk group. The median among those receiving exisulind increased from 5.63 months to 8.84 months while it decreased from 4.49 to 2.39 months in the placebo group. The mean PSA doubling time in the exisulind high-risk group rose from 8.12 to 29.7 months, Dr. Prager reported, while that in the placebo arm dropped from 7.3 to 4.9 months.
There was a similar but not significant increase in PSA doubling time in the intermediate-risk group receiving exisulind, compared with those receiving placebo. "As would be expected in a 12-month study, the low-risk patients whose prestudy PSA doubling time exceeded 20 months did not show significant change during treatment," she said.
Analysis of PSA-progression-free survival showed a trend toward longer time to PSA progression in high-risk patients receiving exisulind, Dr. Prager noted. During the 12 months on study, 22% of the exisulind patients and 67% of placebo patients in the high-risk group developed progressive disease.
"The incidence of disease progression was too low in the intermediate- and low-risk groups to show any significant differences between the treatment groups," she said.
Adverse Events
Abdominal pain and dyspepsia were the only adverse effects of exisulind that were considered severe, Dr. Prager said. Dyspepsia caused drug discontinuation in 2 patients. Liver enzymes were elevated in 17 patients, but this effect was reversible, she reported. "No patients," she said, "discontinued treatment due to liver enzyme abnormalities."
A nonsteroidal anti-inflammatory drug, exisulind does not inhibit COX I and II, Dr. Prager said. "The gastrointestinal and renal toxicity associated with chronic nonsteroidal use," she said, "therefore are not side effects seen with this class of drugs."
The findings in the completed trial, Dr. Prager told ONI, "point to the need for a larger multicenter phase III study in high-risk patients." An open-label study of exisulind is currently being conducted, she reported, with some patients receiving 600 mg daily.
