MMP Inhibitor Is Tested in Refractory Prostate Cancer

ASCO--An oral drug that blocks enzymes that appear to be fundamentalfor tumor spread significantly slowed the rate of rise of PSA in men withadvanced hormone-refractory prostate cancer and may have the potentialto increase survival, Peter Boasberg, MD, reported at the ASCO meeting.

The agent, marimastat from British Biotech, is the first orally availablematrix metalloproteinase (MMP) inhibitor. The MMPs are a family of enzymesthat 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 migrationof cancer cells into lymphatics and blood vessels, and inhibits endothelialcell recruitment," said Dr. Boasberg, of the John Wayne Cancer Center,Santa Monica.

Because the agent is cytostatic rather than cytotoxic, it was not expectedto reduce tumor size but only to inhibit growth. Thus, the rate of riseof PSA was chosen as a primary endpoint.

All of the 88 patients enrolled in this dose-ranging study had rapidlyprogressing refractory prostate cancer (91% with stage IV disease). Allavoided 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 thestudy. At higher marimastat dose levels (10 to 50 mg twice daily), a greaterproportion 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 rateof 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 biologiceffect. The vast majority of the responders are still receiving the drugin a continuation study.

Marimastat was well tolerated, Dr. Boasberg said, with musculoskeletaleffects the dose-limiting toxicity. These symptoms subsided with a drugholiday.

An audience member noted that PSA rate of rise has not been establishedas a surrogate marker for prostate cancer progression and reduction inPSA has not been shown to have an impact on outcome. But Dr. Boasberg counteredthat "in this study, it did. We saw a substantial difference in survivalbased on the velocity of the rise in PSA."