Findings presented at the American Society of Clinical Oncology (ASCO) meeting Saturday, June 4 show that PARP inhibitors may offer a new type of treatment for patient with BRCA-related advanced breast cancer. The Phase III OlympiAD trial demonstrates for the first time that PARP inhibitor olaparib (AstraZeneca’s Lynparza) is superior to chemotherapy for tumor control in this patient population.
PARP—poly (ADP-ribose) polymerase—is an enzyme used by healthy cells to repair themselves. However, when cancer cells use PARP, they extend their growth.
Olaparib selectively binds to and inhibits PARP, preventing it from repairing DNA damage in cancer cells, particularly those cancer cells that have lost BRCA1 or BRCA2 function, according to a statement from Penn Medicine, whose researchers led some of the seminal studies that contributed to the development of the OlympiAD trial.
The phase III OlympiAD trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival for patients treated with olaparib tablets, compared to treatment with physician’s choice of a standard of care chemotherapy (capecitabine, vinorelbine, eribulin).
“Although previous studies suggested olaparib could benefit patients with advanced breast cancers, we are now reporting that olaparib improves progression-free survival better than standard chemotherapy,” said study co-author Susan Domchek, M.D., executive director of the Basser Research Center for BRCA at the University of Pennsylvania’s Abramson Cancer Center, in a statement. “Based on our previous work, leaders in BRCA research have been advocating for this trial for many years, urging pharmaceutical companies to focus on efforts that are now generating new therapies for our patients.”
An earlier study led by Domchek and colleagues resulted in the first FDA approval of olaparib in 2014 for patients with pretreated BRCA1/2 associated ovarian cancer. That study, a phase II trial published in the Journal of Clinical Oncology, showed olaparib produced an overall tumor response rate of 26 percent in patients with advanced cancers associated with BRCA1 and BRCA2 mutations who had not previously responded to standard therapies.
For the OlympiAD study, researchers randomized 302 patients who had metastatic breast cancer to either take 300 mg olaparib twice a day or receive standard chemotherapy until the cancer worsened or the patient developed severe side effects. All of the women had HER2-negative germline BRCA1 or BRCA2-mutated breast cancer and had up to two prior rounds of chemotherapy for their breast cancer. while Some had previously been given hormone therapy.
The trial showed that tumors shrank in about 60 percent of patients who received olaparib, compared with 29 percent of those who received chemotherapy. Also, patients treated with olaparib had a 42 percent reduction in risk of their disease worsening or death compared to those who received chemotherapy.
The median time to progression was 7 months with olaparib and 4.2 months with chemotherapy.
After progression, the researchers kept track of patients to see how long it would be before the cancer worsened again. Researchers found the time to second progression was also longer in patients receiving olaparib, indicating that the cancers did not return in a more aggressive way once olaparib stopped working. According to a release from ASCO, the study is insufficiently mature to permit a determination if the benefits provided by olaparib translate into prolongation of overall survival at this time.
The findings were presented during the meeting’s plenary session on Sunday by Mark E. Robson, M.D., clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center and principal investigator of the trial.
“This is the first demonstration of improved outcomes with a PARP inhibitor compared to standard treatment in women with BRCA mutation-associated breast cancer,” said Robson. “It is especially encouraging to see that olaparib was effective against triple negative breast cancers that arise in women with inherited, germline BRCA mutations. This type of breast cancer is particularly difficult to treat and often affects younger women.”
“Olaparib will probably be best used early in the course of metastatic breast cancer. It helps preserve patient quality of life, offers the chance to postpone the need for I.V. chemotherapy, and avoids side effects like hair loss and low white blood cell counts,” said Robson.
“These long-awaited findings show that this new class of treatment can deliver better results for women with BRCA-positive breast cancer,” said ASCO President Daniel F. Hayes, MD, FACP, FASCO. “What’s remarkable is that we are now able to not only tailor breast cancer treatment based on the genetic changes in the tumor, but also on the inherited factors driving its development.”
Filed Under: Drug Discovery