While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients with <em>BRCA</em>-positive breast cancers, according to Nadine M. Tung, MD.
Nadine M. Tung, MD
While PARP inhibitors have demonstrated success in ovarian cancer previously, they are finally impacting the treatment paradigm for patients withBRCA-positive breast cancers, according to Nadine M. Tung, MD.
The FDA approved olaparib (Lynparza) in January 2018 for treatment of patients with germlineBRCA-positive, HER2-negative metastatic breast cancer who have received a prior treatment of chemotherapy. Based on results from the phase III OlympiAD trial, olaparib reduced risk of disease progression or death by 42% and improved progression-free survival (PFS) by 2.8 months versus standard chemotherapy in previously treated patientsBRCA-positive, HER2-negative disease. These promising results led to the FDA approval.1
Phase III findings also demonstrated potential benefit with talazoparib, another PARP inhibitor. Talazoparib was reduced the risk of disease progression or death by 46% in patients withBRCA-positive advanced breast cancer in the EMBRACA trial.2At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib versus 5.6 months with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71;P<.0001).
In an interview withTargeted Oncology,Tung, associate professor of medicine at the Harvard Medical School and director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, discussed the emerging role PARP inhibitors have for patients withBRCA-positive breast cancer and the importance of genetic testing.
TARGETED ONCOLOGY: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 germlineBRCAmutations 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 germlineBRCA1/2mutation and have seen chemotherapy at some pointeither in the initial setting, adjuvant, neoadjuvant, or metastatic setting
TARGETED ONCOLOGY:What other PARP inhibitors are being investigated?
Tung: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.
TARGETED ONCOLOGY:Are there any thoughts of bringing PARP inhibitors to earlier lines of therapy?
Tung:Both of the studies I mentioned were for patients who had seen standard chemotherapyanthracyclines 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 germlineBRCAmutations who have higher risk of disease after they complete standard chemotherapy and local therapy.
TARGETED ONCOLOGY:Could this benefit patients without BRCA mutations?
Tung:That is an important goal we are working on. We want to find patients who do not have germlineBRCAmutations, 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 germlineBRCAmutations.
GermlineBRCA-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 withBRCA1/2in that DNA repair pathway.
In metastatic prostate cancer, patients with germline or somatic mutations in the other genes, such asATM, respond to PARP inhibitors. That approach is being looked at with breast cancer. We are looking at patients who have some other mutations, such asATMandPALB2.
TARGETED ONCOLOGY:How do you typically identify these mutations?
Tung:For some patients, we do germline testing. If they have a personal or family history that is suggestive of having an inheritedBRCAmutation, we do multigene panels. For many patients, we are rarely just testing forBRCA1/2. 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 aBRCAmutation that do not have an inherited germline mutation.
It is important to say that any time aBRCAmutation is found in the tumor, that should trigger germline testing so that it is known whether the patient has an inherited mutationas 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 aBRCAmutation, a patient should undergo germline testing if they qualify for it.
TARGETED ONCOLOGY:When is it best to conduct germline testing?
Tung:Even though PARP inhibitors are not yet approved in an earlier setting, if a patient qualifies for germlineBRCAtesting, 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.
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.
TARGETED ONCOLOGY:Is there anything else you would like to add?
Tung: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 asBRIP1, RAD51C,andRAD51D,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.