Findings from a phase III clinical trial of about 300 women may introduce poly ADP ribose polymerase (PARP) inhibitors as a new type of treatment for breast cancer. Compared to standard chemotherapy, the oral targeted medicine olaparib (Lynparza) reduced the chance of progression of advanced, BRCA-related breast cancer by 42%, delaying progression by approximately 3 months. These data were presented by Robson et al today during the Plenary Session at the 2017 ASCO Annual Meeting (Abstract LBA4).
“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 lead study author Mark E. Robson, MD, Clinic Director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering Cancer Center. “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.”
Up to 3% of all breast cancers occur in people with inherited changes in genes BRCA1 and BRCA2. These changes lower the cell’s ability to repair damaged DNA. Olaparib blocks other key players in the cell’s DNA repair machinery, PARP1 and PARP2. Because of their underlying defect in DNA repair, cancer cells with BRCA mutations are particularly vulnerable to treatments that target PARP. Olaparib is already approved by the U.S. Food and Drug Administration for use in women with BRCA-related ovarian cancer.
“This study is proof of the principle that breast cancers with defects in a specific DNA damage repair pathway are sensitive to a targeted therapy designed to exploit that defect,” said Dr. Robson.
About the OlympiAD Trial
The OlympiAD trial enrolled patients with inherited BRCA mutations who had metastatic breast cancer that was either hormone receptor–positive or triple-negative (estrogen receptor–negative, progesterone receptor–negative, and HER2-negative). Women with HER2-positive breast cancer were not included in this study because there are already very effective targeted treatments for this group.
All patients had up to two prior rounds of chemotherapy for metastatic breast cancer, and those with hormone receptor–positive cancer had received hormonal therapy. The researchers randomly assigned 302 patients to receive olaparib tablets or standard chemotherapy (either capecitabine, vinorelbine, or eribulin [Halaven]) until the cancer worsened or the patient developed severe side effects.
Tumors shrank in about 60% of patients who received olaparib, compared with 29% of those who received chemotherapy. At a median follow-up of about 14 months, patients who received olaparib had a 42% lower chance of cancer progression than those who received chemotherapy. The median time to progression was 7 months with olaparib and 4.2 months with chemotherapy.
After disease progression, the researchers kept track of patients to see how long it would be before the cancer worsened again. 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. The study is insufficiently mature to permit a determination of whether the benefits provided by olaparib translate into prolongation of overall survival at this time.
The most common side effects in the olaparib group were nausea and anemia, whereas low white blood cell counts, anemia, fatigue, and rash on hands and feet were most common in the chemotherapy group. Severe side effects were less common with olaparib, occurring in 37% of patients compared to 50% of those treated with chemotherapy. Only 5% of patients needed to stop olaparib due to side effects. Health-related quality of life was significantly better in the olaparib group.
“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 [intravenous] chemotherapy, and avoids side effects like hair loss and low white blood cell counts,” said Dr. Robson.
Given the relatively small size of the study, it is difficult to tell which subset of patients would benefit the most from olaparib. This is the first of four ongoing phase III clinical trials of PARP inhibitors in breast cancer to report findings. More research is needed to determine how well olaparib works in cancers that worsen despite platinum-based chemotherapy, a standard regimen not included in this study, and whether platinum-based chemotherapy would be useful after cancers worsen despite olaparib.
“These long-awaited findings show that this new class of treatment can deliver better results for women with BRCA-positive breast cancer. 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,” said ASCO President Daniel F. Hayes, MD, FACP, FASCO.
This study was funded by AstraZeneca.
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