Role of PARP Inhibitors in Breast Cancer Continues to Be Refined

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; P <.0001).

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

What other PARP inhibitors are being investigated?

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

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

Could this benefit patients without BRCA mutations?

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.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. 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.

How do you typically identify these mutations?

In metastatic prostate cancer, patients with germline or somatic mutations in the other genes, such as ATM, respond to PARP inhibitors. That approach is being looked at with breast cancer. We are looking at patients who have some other mutations, such as ATM and PALB2. For some patients, we do germline testing. If they have a personal or family history that is suggestive of having an inherited BRCA mutation, we do multigene panels. For many patients, we are rarely just testing for BRCA1/2. We are looking for these other DNA repair genes.

In metastatic patients, we do a lot of tumor somatic testing that looks at targets of therapy. You pick up a lot of germline mutations by testing the tumor in the metastatic setting. There are about 4% of patients with breast cancer whose tumors will have a BRCA mutation that do not have an inherited germline mutation.

When is it best to conduct germline testing?

It is important to say that any time a BRCA mutation is found in the tumor, that should trigger germline testing so that it is known whether the patient has an inherited mutation—as that has other implications for risk management for other cancers and family members. It is also important to say that even if the tumor testing does not show a BRCA mutation, a patient should undergo germline testing if they qualify for it.Even though PARP inhibitors are not yet approved in an earlier setting, if a patient qualifies for germline BRCA testing, they should always have it at initial diagnosis. It has implications for their local treatment, surgery, what chemotherapy is being chosen, prophylactic mastectomies, and risk management. In the initial setting, if someone meets criteria for germline testing, they should always have it.

Is there anything else you would like to add?

At recurrence or at metastatic disease, we are almost always doing tumor testing. If the patient missed it or qualifies for germline testing and never had it, they should get it at that point.There is a lot of debate about how much genetic testing to do in a patient who is diagnosed with breast cancer. Should it just be the high-risk breast cancer genes? Should it be high- and moderate-risk breast cancer genes? Should it be a multigene panel that looks for cancer susceptibility genes for other cancers? I do not think there is complete agreement among experts in this field, but we are increasingly using panels. Identifying the breast cancer susceptibility genes has implications for treatment and surveillance in our own patients, identifying their risks for other cancers, and also for their relatives.

Now that there are some new ovarian cancer susceptibility genes, such as BRIP1, RAD51C, and RAD51D, identifying those mutations warrants a discussion about prophylactic mastectomy in our patients with breast cancer. For me, I am virtually always testing for the breast and ovarian cancer susceptibility genes. However, if the patient and the clinician feel that there is merit in finding other cancer susceptibility genes, then a multigene panel for established cancer risk genes is appropriate.

We know now that when we test patients with breast cancer, we do find Lynch syndrome genes in patients who do not have a personal or family history that would have suggested it. If the patient and clinician feel this is important information, then a multigene panel makes sense.

References

1. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. 2017;377:523-533. N Engl J Med. doi: 10.1056/NEJMoa1706450.
2. Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS6-07.