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Role of PARP Inhibitors in Breast Cancer Continues to Be Refined

Danielle Bucco
Published: Thursday, Apr 19, 2018

Nadine M. Tung, MD
Nadine M. Tung, MD
PARP inhibitors, having shown success in ovarian cancer, have finally made it to the treatment paradigm for patients with BRCA-positive breast cancers, explains Nadine M. Tung, MD.

In January 2018, the FDA approved olaparib (Lynparza) for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. The approval was based on the results from the phase III OlympiAD trial, which showed that olaparib reduced the risk of disease progression or death by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patients BRCA-positive, HER2-negative disease.1

Moreover, encouraging phase III findings were also demonstrated with the PARP inhibitor talazoparib. In the EMBRACA trial, talazoparib was found to reduce the risk of disease progression or death by 46% in patients with BRCA-positive advanced breast cancer.2 At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib compared with 5.6 months with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; <.0001).

In an interview with OncLive, Tung, an associate professor of medicine, Harvard Medical School, director, Cancer Risk and Prevention Program, Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, discussed the role of PARP inhibitors for patients with BRCA-positive breast cancer and the importance of genetic testing.

OncLive: What is the current treatment landscape of PARP inhibitors for patients with breast cancer?

Tung: The newest development is the OlympiAD trial and the FDA approval of olaparib for patients with germline BRCA mutations who have metastatic, HER2-negative breast cancer. The FDA approved use of olaparib in January 2018, so that is available now for patients who have metastatic HER2-negative breast cancer. Those patients also have a germline BRCA1/2 mutation and have seen chemotherapy at some point—either in the initial setting, adjuvant, neoadjuvant, or metastatic setting.

What other PARP inhibitors are being investigated?

Firstly, the OlympiAD trial investigated olaparib compared with nonplatinum standard chemotherapy. Olaparib led to a significant improvement in PFS.

A similar study was presented at the 2017 San Antonio Breast Cancer Symposium using a different PARP inhibitor, talazoparib, in the EMBRACA trial. It was a very similar design with the same population, comparing the PARP inhibitor monotherapy with standard chemotherapy choices. Interestingly, the results were very similar with a significant improvement in PFS by approximately 3 months. It will be interesting to see if a second PARP inhibitor does get FDA approval.

Are there any thoughts of bringing PARP inhibitors to earlier lines of therapy?

Both of the studies I mentioned were for patients who had seen standard chemotherapy—anthracyclines or taxanes—either in the initial or metastatic setting. Now, PARP inhibitors are also being studied in an earlier setting. There are studies, such as OlympiA, looking at [olaparib in] the adjuvant setting for patients with germline BRCA mutations who have higher risk of disease after they complete standard chemotherapy and local therapy. 

Could this benefit patients without BRCA mutations? 

That is an important goal we are working on. We want to find patients who do not have germline BRCA mutations, but whose tumors may be sensitive to PARP inhibitors. The way that investigators are trying to approach that topic is to identify breast cancers that also have the same DNA repair defect as the breast cancers in patients with germline BRCA mutations. 

Germline BRCA-associated breast cancers have a defect in homologous recombination. That is the pathway that repairs double-strand DNA breaks. How can we identify other breast cancers that have this defect? There are various tools being developed. None of them are in clinical use yet, but some of them are interesting. Some look at genomic loss in the tumor, whereas others look at mutational signatures to find those with a defect in homologous recombination. The other approach is to look at patients who either have a germline mutation or whose tumors have a somatic mutation in other genes that work with BRCA1/2 in that DNA repair pathway.




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Community Practice Connections™: 16th Annual International Congress on the Future of Breast Cancer®Sep 29, 20182.0
School of Breast Oncology®: Mid-Year Video Update OnlineSep 30, 20182.0
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