Cancer drug olaparib shows early promise

Posted: July 12, 2010

A novel therapy designed to exploit the renegade power of malignant cells showed remarkable effectiveness against advanced ovarian and breast cancer in two small international studies.

One breast cancer patient who was terminally ill, the most remarkable case of all, continues to enjoy a complete remission of her disease two years after participating in one of the studies at the University of Pennsylvania.

"It's just so amazing," said Patricia Buckles, 61, of Memphis. "It's given me two years of my life that traditional chemotherapy could not. I'll stay on it, Lord willing, as long as my cancer stays asleep."

The experimental drug, a capsule called olaparib, works by making cancer cells even more genetically unstable than they already are. The cancer cells become too defective to survive, like a wobbly chair with only three legs that loses another leg.

Olaparib is being developed by AstraZeneca P.L.C., which has its U.S. headquarters in Wilmington. The company-funded studies were published online last week in the Lancet. But at least five other pharmaceutical companies are racing to develop their own "PARP inhibitors" because the new class promises to work against several kinds of cancer, and to have more tolerable side effects than conventional chemotherapies.

The new studies, led by Andrew Tutt of King's College London School of Medicine, involved researchers from 18 medical centers around the world, including Penn for breast-cancer patients.

Patients, who received either a high or low dose of olaparib, had better response rates on the high dose - another sign that the drug is effective.

All the patients had run out of standard treatment options, and their cancers had metastasized to other organs.

Of 27 breast-cancer patients who got a high dose of olaparib, 11 (41 percent) had tumor shrinkage, and 12 (44 percent) had no tumor growth for at least 23 weeks of the first 24 weeks of study. Of the 27 women on the lower dose, six had tumor shrinkage and 12 had stable disease.

Study coauthor Susan Domchek, director of Penn's Cancer Risk Evaluation Program, called it "an enormous response rate" considering that the women had received at least three prior chemotherapies.

The ovarian cancer study has 33 high-dose patients, of whom 11 (33 percent) had tumor shrinkage and 12 (36 percent) had stable disease. Among 24 low-dose patients, 3 had tumor shrinkage, and 7 had stable disease.

Although PARP inhibitors are still years away from being marketed - larger and longer studies are needed - the early research has generated excitement because "creating drugs that selectively kill cancer cells without harming normal cells is notoriously difficult," said an editorial published a year ago in the New England Journal of Medicine.

PARP (poly adenosine-disphosphate-ribose polymerase) is an enzyme that repairs breaks in either of the two strands of DNA. These breaks can occur as DNA copies itself to create a new cell.

Inhibiting PARP does not appear to harm healthy cells.

But in the cancer cells of women who have inherited mutations in BRCA1 or BRCA2 genes, which also normally repair breaks in the strands of DNA, inhibiting the PARP repair sets up lethal instability, a condition scientists have dubbed "synthetic lethality."

All the women in the new studies had inherited the BRCA1 or BRCA2 mutations, which are linked to 5 percent to 10 percent of all breast and ovarian cancers.

Women with BRCA defects are at high lifetime risk of breast or ovarian cancer, or both, and the diseases tend to strike early and relentlessly. Buckles, for example, had her first mastectomy when she was 33. In 2006, an aggressive new cancer was found in her other breast; despite surgery and chemotherapy, it spread to her lungs.

Thus, olaparib fought her cancer by exploiting the very defect that led it to develop in the first place.

"This is the first time we have been able to take the genetic reason a person has developed cancer and make it a target," Domchek said.

PARP inhibitors are also being studied to treat pancreatic and prostate cancers that are linked to inherited BRCA mutations.

Since numerous other genes can fix DNA breaks - having spare repair tools is one way the cell fights cancer - researchers hope that PARP inhibitors can create synthetic lethality in even more types of cancer.

"PARP inhibitors may be effective in any type of tumor as long as that tumor started because of genetic mutation" that destabilized the cell, Domchek speculated. "It's very exciting from that standpoint."

Buckles - a part-time nurse and grandmother who works out three times a week - is excited by CAT scans that show "no evidence of disease," or NED in medical parlance.

"I love dancing with NED," she quipped.


Contact staff writer Marie McCullough at 215-854-2720 or mmccullough@phillynews.com.

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