Data from the phase III OlympiAD trial demonstrate that, compared to standard chemotherapy, the oral targeted medicine olaparib significantly reduced the chance of progression of advanced, BRCA-related breast cancer by 42%. This translates into a delay in the disease progression of about 3 months (p=0.0009). Interestingly, olaparib was also effective against triple negative breast cancers that arise in women with inherited, germline BRCA mutations, a very difficult to treat type of breast cancer. As such, this study provides proof of principle that breast cancers with defects in the homologous DNA repair mechanism are sensitive to a PARP inhibitor.
Up to 3% of all breast cancers occur in people with inherited changes in BRCA1 and BRCA2, two genes involved in DNA repair mechanisms. 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.
In OlympiAD, 302 patients aged 18 years or older with HER2-negative metastatic breast cancer (hormone receptor positive or triple negative) and a germline BRCA mutation, who had received not more than 2 chemotherapy lines for metastatic disease, were randomized (2:1) to olaparib tablets (300mg po bid) or chemotherapy (21-day cycles of either capecitabine [2500mg/m2 po days 1–14], vinorelbine [30mg/m2 IV days 1 and 8] or eribulin [1.4mg/m2 IV days 1 and 8]). Treatment was continued until objective disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint of the trial was progression-free survival (PFS) assessed by blinded independent central review.
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 (HR[95%CI]: 0.58[0.43-0.80]; p=0.0009). Also the objective response rate was significantly higher with olaparib as compared to chemotherapy: 59.9% vs. 29% (p< 0.001). After a first progression, the researchers kept track of patients to see how long it would be before the cancer worsened again. This time to second progression was also longer in patients receiving olaparib (HR[95%CI]: 0.57[0.40, 0.83], p< 0.01), indicating that the cancers did not return in a more aggressive way once olaparib stopped working. The data for overall survival were not yet mature.
Grade ≥3 adverse events (AE) occurred in 36.6% and 50.5% of olaparib and chemotherapy patients, with AEs leading to discontinuation in 4.9% and 7.7% of patients, respectively. 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. The health-related quality of life was significantly better with olaparib than with chemotherapy (p=0.0035). Based on the latter, the authors suggested to use olaparib early on in the treatment journey. It helps to 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.
In summary, this is the first demonstration of improved outcomes with a PARP inhibitor compared to standard treatment in women with BRCA mutation-associated breast cancer. 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.
Robson M, Im S-A, Senkus E, et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Presented at ASCO 2017; Abstract LBA4.