In recent years, PARP inhibitors have become a popular class of drugs in oncology therapy, and in particular, for tumors with BRCA gene mutations, PARP inhibitors have been rewarding. Specifically for BRCA gene mutation breast cancer, some studies have shown PARP inhibitors can extend progression-free survival by about 3 months in patients with advanced disease. This article takes a look at what members of the PARP inhibitors are currently available and how they work in the treatment of breast cancer.
Why do PARP inhibitors work against cancer?
The protein encoded by the BRCA gene is an important protein responsible for repairing the DNA errors in human cells. Once the BRCA gene is mutated or disabled, the ability of the cell DNA to repair is greatly diminished, mutations slowly accumulate, and the probability of developing cancer is greatly increased. But tumors carrying BRCA mutated genes also have their own unique weaknesses, and their ability to use BRCA encoded proteins to repair themselves is diminished, and they must rely on other mechanisms to repair damaged DNA, which is when PARP is used.
PARP is also an enzyme in the body, with the full name polyadenylate diphosphate ribosyl polymerase (PARP). This enzyme, like BRCA protein, is also a cellular repairer of DNA damage that occurs during replication.PARP is critical in normal physiological states and is involved in the body’s DNA checking and repair work. However, it was found that PARP is actually expressed very high in tumor cells, which means that during the development of tumors, PARP helps tumor cells to repair themselves, which leads to their exuberant growth. The most important thing is that the tumor cells are not only the most important, but also the most important.
Therefore, inhibiting PARP s DNA repair function is important for eliminating tumors and improving the efficacy of chemotherapy drugs. Researchers have found that PARP inhibitors are valuable in the treatment of BRCA mutant breast cancer.
PARP inhibitor members have had a fruitful fight against breast cancer
In 2014 December 2014, Olaparib, the world’s first PARP inhibitor, was approved for marketing by the U.S. Food and Drug Administration (FDA) for the treatment of advanced ovarian cancer with germline BRCA mutations (gBRCAm) . But this class of drugs did not stop there, and since then there have been many successive successes in the field of breast cancer.
Olaparib
In January 2018, based on the results of a Phase III clinical study, the FDA approved the PARP inhibitor olaparib for the treatment of patients with prior chemotherapy, genetic mutations or deletions, and HER2 (i.e., human epidermal growth factor receptor  nbsp;2)-negative patients with metastatic breast cancer who have received prior chemotherapy.
In this study, enrolled 302 patients with HER2 -negative, metastatic breast cancer with BRCA mutations who had received up to 2 lines of prior chemotherapy. Results Compared with standard single-agent chemotherapy [capecitabine, vinorelbine, or eribulin], the application of olaparib prolonged median progression-free survival by 2.8 months (from 4.2 months to 7  nbsp;months), reduced the risk of disease progression or death by 42%, and increased the remission rate by more than 1 fold (from 28.8% to 59.9%).
Olaparib also demonstrated a better safety profile, with only 2% of patients discontinuing treatment due to adverse reactions (compared with 2.2% in the chemotherapy arm). grade 3 adverse events were also less frequent ( 36.6%, 50.5%, respectively).
Talazoparib
Another PAPR inhibitor Talazoparib although not yet available domestically or internationally, May 2018 29 2018 the FDA has accepted its New Drug application and granted priority review status for consideration for the treatment of BRCA genetic mutation or deletion type and HER2 negative locally advanced or metastatic breast cancer.FDA s decision is based on the results of the Phase III clinical study EMBRACA which was conducted in the United States.
The EMBRACA study enrolled 431 patients with locally advanced or metastatic breast cancer with BRCA gene mutations who had received up to 3 chemotherapies, including platinum.
Results Compared with physician-selected single-agent chemotherapy (capecitabine, vincristine, or eribulin), Talazoparib resulted in a significant extension of median progression-free survival by 3 months (from 5.6 months to 8.6 months) and a median overall survival trend toward longer (from 19.5 months, 22.3 months, respectively, but did not show a difference). At 24 weeks, the objective remission rate in patients receiving Talazoparib also improved significantly by more than 1 fold (from 27.2% to 62.6%), and the absolute clinical benefit rate improved by nearly 1 fold (from 27.2% to 62.6%). nbsp;fold (from 36.1% to 68.6% ).
Overall, patients showed better tolerability of Talazoparib with discontinuations due to adverse effects in the two groups of patients receiving Talazoparib and single-agent chemotherapy at 10% and 8%, respectively, and the incidence of adverse event-related deaths were 3.2% and 2.1%, respectively .
Rucaparib
Rucaparib is the 2nd PARP inhibitor approved for marketing by the FDA and was accelerated by the FDA in December 2016 for the treatment of BRCA gene mutations in treated advanced ovarian cancer. The drug is still being explored in the Phase II clinical study phase in breast cancer.
Among the enrolled 71 patients with BRCA mutated advanced breast or ovarian cancer, the objective remission rates were 15% and 2% for oral and intravenous infusions of Rucaparib respectively, with intravenous infusions of Rucaparib there were also 41% of patients with stable disease for ≥12 weeks, and there were 3 patients with stable disease for even more than 52 weeks. Of the 23 breast cancer patients evaluated, 39% had stable disease for ≥12 weeks. During the study period, patients were well tolerated, with the most common adverse reactions being fatigue (51%) and nausea (36%), and no serious grade 4/5 adverse reactions.
Based on the small studies available, the role of Rucaparib in breast cancer is less than ideal and needs further study. Additional studies of Rucaparib in BRCA mutant advanced breast cancer are ongoing ( NCT02505048), and investigators are also exploring its use in triple-negative breast cancer (NCT03542175, NCT01074970. NCT03101280).
Niraparib
As the third inhibitor of PARP to be approved for marketing by the FDA Niraparib is currently indicated for use in ovarian cancer that has recurred after prior platinum-based chemotherapy.Niraparib s exploration in breast cancer is only The study is just beginning.
In in vitro trials, Niraparib increased sensitivity to radiotherapy in breast cancer cells, suggesting that investigators can further evaluate the role of Niraparib in combination with radiotherapy in breast cancer.
A phase III clinical study of Niraparib in patients with HER2 negative, BRCA mutated advanced breast cancer is ongoing ( NCT01905592) and the results are expected to be revealed. Investigators are also exploring the role of Niraparib in combination with multiple agents such as targeted therapy and immunotherapy (NCT03368729, NCT03154281, NCT02657889), in more types of breast cancer such as triple-negative breast cancer (NCT02657889), and in additional uses in breast cancer, such as in the neoadjuvant treatment of HER2 negative, BRCA mutated breast cancer ( NCT03329937).
In addition, studies have found that the PARP inhibitors, Veliparib and Iniparib, are also effective in the treatment of triple-negative breast cancer.
Summary
The first PARP inhibitor, olaparib, has been FDA approved for the treatment of BRCA mutated metastatic breast cancer breast cancer, extending median progression-free survival by 2.8 months compared to standard single-agent chemotherapy, and reducing the risk of disease progression or death by Talazoparib also prolonged median progression-free survival by 3 months and significantly improved objective remission rates by more than 1 fold at 24 weeks in this group of patients.PARP inhibitors have been shown to be effective in BRCA The role of PARP inhibitors in the treatment of metastatic breast cancer with gene mutations is encouraging.
On the other hand, researchers are still exploring more PARP inhibitors for more applications in breast cancer. Researchers have even identified many “BRCA mutation-like tumors” that do not have a mutation in the BRCA gene, but have a similar pathogenesis, and the role of PARP inhibitors in these tumors is worth exploring.
Expect more and more breast cancer patients to benefit from new drugs like PARP inhibitors!