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“Patients were having to take lots of pills a day to get the appropriate dose,” said Dr. Kristin Zorn, a surgical oncologist at Magee-Womens Hospital of UPMC in Pittsburgh. Zorn is a principal investigator for a study involving Veliparib, a PARP inhibitor being developed by Abbott Laboratories. She said the ideal dose in her Phase II trial is turning out to be much higher than originally thought, but that the study is still enrolling ovarian cancer patients.
The PARP (poly ADP-ribose polymerase) enzyme fixes damage to cells, whether cancerous or not, allowing them to continue to multiply. By interfering with that repair process, PARP inhibitors such as Olaparib and Veliparib make it harder for cancer cells with an abnormal BRCA gene to repair themselves. As a result, the tumor cells accumulate DNA damage, leading to their death.
The potential benefit of PARP inhibitors for patients who carry a BRCA mutation has led to intense interest among this group. In January, breast cancer patients and their advocates were deeply disappointed when Sanofi-Aventis announced that the Phase III trial of its PARP inhibitor, Iniparib, had failed to achieve its “primary survival endpoints”— measurements at a study’s end to see if a given treatment worked. That trial focused on patients with newly diagnosed “triple negative” breast cancer, which does not respond to hormonal treatments.
“Three quarters of BRCA1 breast cancers, especially if [patients] are under the age of 50, are triple negative,” said Daly, adding that, for BRCA2 carriers, the numbers are about 20% to 25%.
Sue Friedman, a 14-year survivor of hereditary breast cancer, is executive director of Facing Our Risk of Cancer Empowered (FORCE), which advocates for those affected by hereditary breast and ovarian cancer. She has watched with frustration the fitful progress of these drugs and contends their stymied path to approval stems, in part, from the failure to design a trial focused solely on BRCA carriers, whom researchers initially had in mind when developing the medicines.
This decision “may have contributed to the fact that the larger studies didn’t meet their primary endpoint,” said Friedman. “My concern is that it may be a while before other companies will develop a new therapy for this community because of the challenges that have been facing PARP inhibitors.”
Zorn, however, contends that large-scale studies with both BRCA carriers and non-carriers will yield the greatest dividends. “We don’t know that the population with BRCA mutations is the only one that benefits from PARPs. We all win if we identify the largest possible group of patients who benefit from a practical standpoint; a pharma company is less likely to pursue FDA approval if only a small select group of patients are candidates.”
She continues to be optimistic about the research, particularly in its value for ovarian cancer, a disease for which there is no effective maintenance medicine since patients invariably become resistant to the treatments. Every year nearly 14,000 women in the U.S. die of the disease.
“Although the path to approval has become much more complicated,” said Zorn, “the value of what we have learned is undiminished.”
Karen Iris Tucker is a freelancer who writes about health, culture and entertainment.Contact her at firstname.lastname@example.org