Olaparib is an oral PARP inhibitor, the full name of which is poly(adenosine diphosphate ribose) polymerase inhibitor.In 2014 Olaparib was approved for marketing by the U.S. Food and Drug Administration (FDA) for the treatment of BRCA germline mutations (gBRCAm) in In 2018 early 2018, the U.S. FDA approved the drug for the treatment of BRCA germline mutated 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, related 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 are unable to repair this DNA damage and will result in cell death.
Theoretically, olaparib could treat all cancers carrying 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
People selected for olaparib for solid tumors all have BRCA1/2 gene mutations. In an early clinical study, the drug showed good antitumor activity. 19 patients with ovarian, breast, or prostate cancer, 12 had clinical benefit, with maintenance up to 19 months.
There were 3 patients with BRCA2 gene mutation breast cancer in the study, and 1 achieved complete remission with olaparib treatment with a maintenance time of more than 15 weeks. The therapeutic potential of olaparib in BRCA mutated tumors opens up new pathways for subsequent breast cancer-related research.
In a separate phase II study, there were 298 patients with recurrent cancer that was positive for germline mutations in the BRCA gene, including 62 advanced breast cancers that had received 3 times or more chemotherapy. After olaparib treatment, the overall remission rate for patients was 26.2%, and the remission rate for breast cancer patients was 12.9%. Common adverse effects included fatigue, nausea, and vomiting, with 54% of patients experiencing grade ≥3 adverse events.
While the above study was not specific to breast cancer, it is clear that olaparib showed some anticancer effects with a good safety profile for the treatment of BRCA mutation-positive breast cancer.
BRCA-mutant breast cancer has shown 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 BRCA1/2 mutant advanced breast cancer were treated with olaparib. The remission rates for patients were 41% and 22% with higher and lower doses of treatment, respectively. The study suggests that olaparib holds promise as 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 BRCA1/2 gene mutation-positive patients were enrolled, of whom 2/3 were given olaparib and 1/3 received single-agent chemotherapy such as capecitabine, vincristine, or eribulin.
The results showed that the median progression-free survival of patients on olaparib was significantly longer by 2.8 months (from 4.2 months to 7 months) compared with patients receiving standard chemotherapy, and that olaparib reduced the risk of disease progression or patient death by 42% compared with chemotherapy , and patients also had significantly higher remission rates than chemotherapy ( 59.9%, 28.8%, respectively).
In addition, with regard to safety, the incidence of adverse events during treatment with olaparib was much lower than in chemotherapy patients ( 36.6%, 50.5%, respectively), and the proportion of treatment interruptions due to adverse drug reactions was lower with olaparib.
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 the quality of life of patients. Subsequently, the FDA approved olaparib for breast cancer indications.
A new exploration
The quest doesn’t stop there, as studies of olaparib have expanded to include more patients with triple-negative breast cancer in addition to BRCA1/2 gene mutated 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, the Olaparib Phase III clinical study for BRCA1/2 mutant, HER2 negative, high-risk early-stage breast cancer is undergoing patient enrollment, with plans to enroll 200 patients in China (No. CTR20140905) .
The China Breast Cancer BRCA gene mutation survey showed that the BRCA mutation rate was 27.0% in the group of patients diagnosed with familial breast cancer before the age of 40 years.BRCA1/2 gene mutations are a prerequisite for the use of PARP inhibitors, so to benefit from drugs such as olaparib, genetic The BRCA1/2 gene mutation is a prerequisite for the use of PARP inhibitors.
Summary
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 on olaparib are ongoing, and we look forward to the early use of this drug in Chinese breast cancer patients.