Olaparib is an oral PARP inhibitor with the full name polyadenosine diphosphate ribose polymerase inhibitor.In 2014, Olaparib was approved for marketing by the FDA for the treatment of advanced ovarian cancer with germline mutations in the BRCA gene (gBRCAm).In early 2018, the FDA approved the drug for the treatment of BRCA gene mutation in HER2-negative advanced breast cancer.
In August 2018, olaparib was launched in China for the treatment of recurrent ovarian cancer, and although it has not yet received a breast cancer indication, studies are in full swing.
How does olaparib work as an anti-cancer agent?
PARP plays an important role in DNA break repair, and breast cancers that carry the BRCA1/2 germline mutation gene have a functional defect in DNA damage repair.
Olaparib, a PARP inhibitor, causes tumor cell DNA damage to accumulate, triggering DNA breaks. tumor cells in patients with BRCA 1/2 germline mutations cannot repair this DNA damage and will result in cell death.
Theoretically, olaparib could treat all cancers that carry the BRCA1/BRCA2 gene mutation, including, of course, breast cancer. However, theory is still theory and needs to be tested in practice.
Olaparib may benefit multiple tumors
Olaparib for solid tumors was selected in a population with a BRCA1/2 gene mutation. In an early clinical study, the drug showed good antitumor activity. 12 of 19 patients with ovarian, breast, or prostate cancer had clinical benefit, including maintenance for up to 19 months.
There were 3 patients with BRCA2 gene mutation breast cancer in the study, and 1 achieved complete remission with olaparib for more than 15 weeks. The therapeutic potential of olaparib in BRCA-mutated tumors opens up new avenues for subsequent breast cancer-related research.
In another phase II study, there were 298 patients with recurrent BRCA germline mutation-positive cancer, including 62 with advanced breast cancer who had received 3 or more chemotherapy treatments. After olaparib treatment, patients had an overall remission rate of 26.2% and a 12.9% remission rate in breast cancer patients. Common adverse events included fatigue, nausea, and vomiting, with 54% of patients experiencing grade ≥3 adverse events.
While these studies were not specific to breast cancer, it is clear that olaparib has shown some anticancer effects and a good safety profile in treating BRCA mutation-positive breast cancer.
BRCA-mutant breast cancer showed promising benefit
Based on the previous exploration, the investigators continued to investigate the future of olaparib in the treatment of breast cancer.
In a proof-of-concept trial, 54 patients with advanced BRCA1/2 gene mutation breast cancer were treated with olaparib. The remission rates were 41% and 22% with higher and lower doses, respectively. The study suggests that olaparib may be a new treatment option in breast cancer.
In 2017, the New England Journal of Medicine, a top international medical journal, reported on a phase III clinical trial that laid the groundwork for olaparib in advanced breast cancer. 302 patients with positive BRCA1/2 gene mutations were enrolled, 2/3 of whom were given olaparib and 1/3 received single-agent chemotherapy such as capecitabine, vincristine, or eribulin (Eribulin).
The results showed that median progression-free survival was significantly longer by 2.8 months in patients treated with olaparib compared with those treated with standard chemotherapy (from 4.2 months to 7 months), that olaparib reduced the risk of disease progression or patient death by 42% compared with chemotherapy, and that patients had significantly higher remission rates than chemotherapy (59.9% versus 28.8%, respectively).
In addition, in terms of safety, the incidence of adverse events during treatment with olaparib was much lower than in patients treated with chemotherapy (36.6%, 50.5%, respectively), and the rate of interruption of treatment with olaparib due to adverse drug reactions was lower.
In this large study, olaparib outperformed chemotherapy in terms of both efficacy and safety for the treatment of metastatic breast cancer with a BRCA1/2 germline mutation, and helped improve quality of life for patients. Subsequently, the FDA approved olaparib for breast cancer.
A new exploration
The quest does not stop there. In addition to BRCA1/2 gene mutant breast cancer, studies of olaparib have expanded to include more patients with triple-negative breast cancer. Of interest is the clinical trial involving Chinese breast cancer patients: the Phase III study of olaparib for BRCA1/2 mutated, HER2-negative advanced breast cancer has completed enrollment (No. CTR20140906).
In addition, a phase III clinical study of olaparib for BRCA1/2 mutant, HER2-negative, high-risk early-stage breast cancer is enrolling 200 patients in China with the opportunity to receive olaparib treatment (No. CTR20140905).
A survey of BRCA gene mutations in breast cancer in China showed a BRCA mutation rate of 27.0% in a cohort of patients diagnosed with familial breast cancer before the age of 40. BRCA1/2 gene mutations are a prerequisite for PARP inhibitors, so genetic testing is imperative to benefit from drugs like olaparib.
Summary
The available evidence suggests that olaparib has better efficacy and safety in treating metastatic breast cancer with BRCA1/2 gene mutations. Relative to chemotherapy, olaparib prolonged progression-free survival by 2.8 months and reduced the risk of disease progression or death by 42%.
Other clinical studies of olaparib are ongoing, and we look forward to its early use in Chinese breast cancer patients.