Testing a New Drug in Advanced BRCA-related Cancer
Name of the Trial
Phase I Study of AZD2281 and Carboplatin in Patients with BRCA1/BRCA2-associated or Familial Metastatic or Unresectable Breast and/or Ovarian Epithelial Cancer (NCI-08-C-0092). See the protocol summary.
Dr. Elise Kohn, NCI Center for Cancer Research
Why This Trial Is Important
The genes BRCA1 and BRCA2 are human tumor suppressor genes. People who inherit a mutated form of either of these genes are at much higher risk of developing certain types of cancer, including breast and ovarian cancer, than people in the general population. Previous research has indicated that cancers associated with BRCA gene mutations may be particularly sensitive to drugs that target a protein called PARP1.
PARP1 is required for one of several processes that cells use to repair damaged DNA. The proteins produced by normally functioning BRCA genes participate in a different DNA repair process. When either process is blocked, the other appears to pick up the slack. Scientists speculated, therefore, that cells with defective BRCA proteins might be especially vulnerable to drugs that inhibit PARP1. Indeed, laboratory and animal studies have shown that PARP1 inhibitors are much more toxic to cells with BRCA gene mutations than to cells with normal BRCA genes. Early clinical studies of this therapeutic approach have yielded promising results.
In this clinical trial, women with advanced breast or ovarian cancer who carry a known BRCA gene mutation or who have a strong family history of these diseases (and are, therefore, likely to carry such a mutation) will be treated with a new drug called AZD2281 (olaparib) together with the chemotherapy drug carboplatin. AZD2281 inhibits PARP1, and preclinical studies suggest that combining it with a platinum-based drug, such as carboplatin, may lead to better outcomes.
"The idea is to stress the cancer cells with carboplatin, which is known to be effective in ovarian cancer and possibly some breast cancers, while blocking DNA repair pathways," said Dr. Kohn. "Mutation carriers have increased susceptibility to platinum drugs, and we hypothesize that they will be even more susceptible with PARP1 inhibition.
"Since this is a phase I trial, we are looking primarily at safety, but we hope to see responses as well," she added.
The researchers are also planning to expand the trial to include women with triple-negative breast cancer or high-grade serous ovarian cancer who do not have BRCA-related or familial breast or ovarian cancer. Some studies have suggested that these women may also benefit from treatment with PARP1 inhibitors.