The chemotherapeutic agent olaparib has given promising results against advanced breast cancer in a group of women with BRCA1 (breast cancer 1, early onset) or BRCA2 (breast cancer 2, early onset) mutations in a phase two clinical trial conducted at 16 centers in Australia, Europe, and the U.S.

Olaparib is an inhibitor of the enzyme Poly ADP ribose polymerase (PARP). Patients with BRCA1/2 mutations may be genetically predisposed to develop some forms of cancer, and are often resistant to other forms of cancer treatment. Yet, this may also burden their cancers with a unique vulnerability, as these cancer cells have increased reliance on PARP to repair their DNA and enable them to continue dividing. This means that drugs that selectively inhibit PARP may be of significant benefit in patients whose cancers are susceptible to this treatment.

In the current study, a group of 54 women 18 years old or older with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were placed into one of two test cohorts. The first cohort was treated with 400 mg oral olaparib twice daily and the second group of 27 patients received 100 mg oral olaparib twice daily.

Results published in the July 6, 2010, online edition of the journal the Lancet revealed that the higher dose appeared to have more activity against the disease, with one patient (4%) having a complete resolution of her tumor and ten (37%) showing substantial tumor shrinkage. Another 12 (44%) women had stable disease or some tumor shrinkage, but not enough to be considered a partial response by standard criteria. In the low dose group, six (22%) patients showed substantial shrinkage and 12 (44%) had some tumor shrinkage or stable disease.

Adverse side effects in the cohort given 400 mg twice daily were fatigue, nausea, vomiting, and anemia. The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea and fatigue.

"This is the first time that we have been able to take the genetic reason a person has developed cancer and make it a target,” said contributing author Dr. Susan M. Domchek, associate professor of medicine at the University of Pennsylvania School of Medicine (Philadelphia, USA). "Most of the time we look at what is going on in the tumor itself and then figure out how to target it. But in this situation, the women all had an inherited mutation in either the BRCA1 or BRCA2 gene and we could exploit that weakness in the tumor. It is a strategy that may cause fewer side effects for patients.”

"If you put too much stress on the cancer cell, it cannot take it, and it falls apart,” said Dr. Domchek. "These drugs may be very potent in tumor cells and much less toxic in normal cells. That is important from the perspective of cancer treatment. This is a different way of looking at cancer therapeutics. In oncology, this is really one of the first times that we have seen drugs being developed on the basis of inherited susceptibility – and that may open up a whole new avenue of drug development.”

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