New Cancer Drug Fights Tumors in Those With BRCA Mutations

WEDNESDAY June 24, 2009 -- A new cancer drug called olaparib worked well in an early clinical trial against breast, ovarian and prostate cancers in individuals who were genetically vulnerable to developing these malignancies.

Women who carry BRCA1 and BRCA2 gene mutations are susceptible to developing breast and ovarian cancer, and among men these mutations are related to an increased risk for prostate cancer, the British researchers noted.

Olaparib works differently than other cancer drugs in that it blocks Poly(ADP-ribose) polymerase (PARP), a protein involved in DNA repair. Healthy cells use PARP to repair themselves, but cancer cells do the same, the scientists explained.

"This is an entirely new class of drugs," said Dr. J. Dirk Iglehart, from the department of surgery at Brigham and Women's Hospital and the department of cancer biology at the Dana-Farber Cancer Institute in Boston, and co-author of an accompanying journal editorial.

When you disable PARP, you prevent the cell from repairing itself, he said, and cancer cells that are deficient in BRCA are much more sensitive to this effect. "When you inhibit PARP, they can't stand it," Iglehart explained.

The report is published online June 24 in the New England Journal of Medicine.

In a phase 1 trial, led by Dr. Johann S. de Bono, from the Institute of Cancer Research at the Royal Marsden NHS Foundation Trust in Sutton, U.K., the scientists treated 60 men and women who were carriers of the BRCA1 or BRCA2 mutations, or had a family history of BRCA-related cancer, with olaparib. All of the patients had either breast, ovarian, prostate, colorectal, melanoma, sarcoma or other cancers.

In this group, there were only a few adverse side effects and they were easily reversed by lowering the dose of the drug, the study noted.

Next, de Bono's team tried the drug on a smaller group of patients, all of whom were confirmed carriers of the BRCA1 or BRCA2 mutation. Those patients received 200 milligrams of olaparib twice a day.

The researchers found that olaparib was absorbed quickly, was eliminated from the body quickly, and had mild side effects. In addition, among people with the BRCA mutations the drug shrunk tumors in breast, ovarian and prostate cancer.

"Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has anti-tumor activity in cancer associated with the BRCA1 and BRCA2 mutation," the team concluded.

Iglehart thinks that combining a PARP inhibitor with chemotherapy drugs that damage DNA might make the drug even more effective. "You might then push cancers over the cliff that would be only susceptible to a PARP inhibitor," he said.

In addition, "PARP inhibitors may be used for tumors that Herceptin or tamoxifen are totally incapable of treating," he said. "That's true for ovarian cancer, too. There is nothing to treat that disease."

Two other trials of PARP inhibitors, which were reported on during the American Society of Clinical Oncology annual meeting in June, also found that they were effective in treating breast cancer.

In one trial where PARP inhibitors were combined with standard chemotherapy, there was almost a doubling of survival -- from 5.7 months with chemo alone to 9.2 months when the PARP inhibitor BSI-201 was added, as well as about a 60 percent reduction in the risk of dying from the disease. There were also no additional side effects.

The second PARP inhibitor trial involved 54 women with advanced breast cancer who carried the BRCA mutations. In this trial, 41 percent of patients saw their tumors disappear. There was a slightly lower response rate in the lower-dose group. Mild nausea and fatigue were the most common side effects.

"The drugs are given orally, and it still remains a question as to whether the drugs' benefits will extend beyond this narrow patient population," noted Dr. Eric Weiner, chief of women's cancers at the Dana-Farber Cancer Institute.

"These two studies are very exciting," Dr. Kelly Marcom, a breast oncologist with Duke Comprehensive Cancer Center and director of the Duke Hereditary Cancer Clinic in Durham, N.C., said. "It speaks to a really clever understanding of the biology of the cancer."

More information

For more information on BRCA1 and BRCA2 cancer, visit the U.S. National Cancer Institute.

Posted: June 2009


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