ASCO--An oral drug that blocks enzymes that appear to be fundamental for tumor spread significantly slowed the rate of rise of PSA in men with advanced hormone-refractory prostate cancer and may have the potential to increase survival, Peter Boasberg, MD, reported at the ASCO meeting.
The agent, marimastat from British Biotech, is the first orally available matrix metalloproteinase (MMP) inhibitor. The MMPs are a family of enzymes that break down the basement membrane and the extracellular matrix.
Marimastat was designed to restrict cancer growth by several mechanisms. "It prevents invasion of the surrounding local tissue, prevents migration of cancer cells into lymphatics and blood vessels, and inhibits endothelial cell recruitment," said Dr. Boasberg, of the John Wayne Cancer Center, Santa Monica.
Because the agent is cytostatic rather than cytotoxic, it was not expected to reduce tumor size but only to inhibit growth. Thus, the rate of rise of PSA was chosen as a primary endpoint.
All of the 88 patients enrolled in this dose-ranging study had rapidly progressing refractory prostate cancer (91% with stage IV disease). All avoided hormonal therapy in the four weeks prior to initiation of the study, as well as antiandrogens, to prevent a withdrawal response.
Overall, PSA rate of rise fell from a median of 53% to 29% during the study. At higher marimastat dose levels (10 to 50 mg twice daily), a greater proportion of patients had a decline (58% versus 34% at lower dose levels), he said.
Among those who achieved a biologic effect (decrease in the PSA rate of rise of 25% or more), median survival has not been reached at 400 days, compared with 260 days median survival in those who did not achieve a biologic effect. The vast majority of the responders are still receiving the drug in a continuation study.
Marimastat was well tolerated, Dr. Boasberg said, with musculoskeletal effects the dose-limiting toxicity. These symptoms subsided with a drug holiday.
An audience member noted that PSA rate of rise has not been established as a surrogate marker for prostate cancer progression and reduction in PSA has not been shown to have an impact on outcome. But Dr. Boasberg countered that "in this study, it did. We saw a substantial difference in survival based on the velocity of the rise in PSA."