Expert Discusses Promise of Olaparib/Durvalumab Combo in BRCA+ Breast Cancer

Susan Domchek, MD

Susan Domchek, MD

Patients with hereditaryBRCA-related breast cancer may have new treatment options in the near future, according to new findings presented at the 2017 San Antonio Breast Cancer Symposium (SABCS).¹

In results from the phase II MEDIOLA trial, the PARP inhibitor olaparib (Lynparza) in combination with durvalumab (Imfinzi), an immunotherapy agent, demonstrated an 80% disease control rate at 12 weeks for pretreated patients withBRCA1/2-mutated, HER2-negative metastatic breast cancer. Olaparib was recently approved by the FDA as a single-agent therapy for the treatment of patients with germlineBRCA-positive, metastatic breast cancer. This approval was based on results from the phase III OlympiaAD trial (NCT02000622).²

During an interview withTargeted Oncologyat SABCS, Susan Domchek, MD, executive director of the Basser Center for BRCA at Penn Medicine’s Abramson Cancer Center, discussed the evolving treatment landscape for patients withBRCA­-related,metastatic breast cancer.

TARGETED ONCOLOGY:Can you provide an overview of the MEDIOLA trial?

Domchek:The MEDIOLA trial is a study ofBRCA1andBRCA2mutation carriers. Here, we are presenting the data on those individuals with metastatic breast cancer. Twenty-five patients received olaparib (Lynparza), which is a PARP inhibitor, and durvalumab, which is a type of immunotherapy drug.

TARGETED ONCOLOGY: What were the results of the study?

Domchek:In the first 25 patients in this study, there was an 80% clinical benefit rate at 12 weeks. This suggests that this may be an active and important combination in this group of patients. What we don't know is how much the immune agent enhances the benefit of the olaparib, because we do know that olaparib can be an effective drug in this particular patient population.

TARGETED ONCOLOGY:What was the toxicity profile?

Domchek:The good news is that the toxicity profile was not changed based on what we know of each of those agents independently. One of the other pieces of work that I'm presenting at SABCS is looking at the tolerability of olaparib in individuals withBRCA1/2mutations. The toxicity profile is very well established. There is some initial nausea that fades over time. There is also some anemia, which can be quite readily managed. In the MEDIOLA trial, with the addition of durvalumab, we didn't see any enhanced toxicity of the olaparib and we saw the expected toxicities of an immune agent.

TARGETED ONCOLOGY:Is there further research you would like to see done on this topic?

Domchek:What we really need to understand are the predictors for response to these sorts of combinations. We need to know whether or not we get a more prolonged response as a benefit of combining the two. Meaning that the response we get from olaparib is now extended because we have also added this immune agent. We would really like to know more about the correlative science, whether or not there are pretreatment predictors that can help us figure this out. We haven't really gotten to that yet.

TARGETED ONCOLOGY:Where are we currently regarding biomarkers and predicting response to different agents?

Domchek:What we know in breast cancer, particularly in metastatic breast cancer, is that knowledge of estrogen receptor status can help determine certain types of treatment. Patients with HER2 + disease get other types of treatment. What has been really exciting this year is that knowledgeBRCA1/2mutations can put you in a different direction. There are a lot of other promising biomarkers and promising drugs that are out there, and we look forward to them being in the clinics so that we can use them.

Then we are going to have to understand the best approach to asses all of those different pieces. There is a drug called pembrolizumab (Keytruda), which is approved by the FDA regardless of tumor site as long as the tumor is microsatellite-instability high (MSI-H). Even though that doesn't happen often with breast cancer, if it does, that would be an additional agent that we can use.

TARGETED ONCOLOGY:What advice can you give to oncologists in large research institutions who need to navigate these new advances in breast cancer?

Domchek:At this time, particularly related toBRCA1/2mutations, we know that most of the patients can be identified by using the National Comprehensive Center Network (NCCN) criteria for who should get genetic testing. A lot of those individuals are not getting genetic testing right now. This is an important aspect, not only for risk assessment and disease prevention, but now it also has an important therapeutic component. We do not want to miss out on those individuals. The next step will be how to rapidly test individuals who don't have an obvious risk to have aBRCA1/2mutation in the context of these other biomarkers that we are discussing.

TARGETED ONCOLOGY:What are some barriers patients are facing who are unable to get genetic testing?

Domchek:It is a number of different elements. We are pretty good at [testing] individuals that are young and developed their breast cancer at an early age. Many of them do go through genetic testing and that is terrific. What we want to focus on is, for instance, people who are older but have a family history. Some of the newer criteria in the NCCN include a family history of high-grade prostate cancer and pancreatic cancer. That is not necessarily something that people have in their heads yet. It is also really important to acknowledge that people of Ashkenazi Jewish ancestry are at higher risk. We also have less testing in underrepresented minorities. It is a matter of identifying individuals, and then decreasing the barriers to get testing.

A lot of people are working on different models to decrease those barriers. It doesn't help if you have a 6-month wait to a see a genetic counselor. That's not an effective strategy. A lot of people are working on better ways to do this.

TARGETED ONCOLOGY:As PARP inhibitors move into the breast cancer sphere, do you think that genetic testing will be more important and more widely used?

Domchek:Absolutely, and that is why I think that developing these streamline models for testing is a very important component and is beyond breast cancer. All ovarian cancer patients should haveBRCA1/2mutation testing. Individuals with pancreatic cancer and prostate cancer can also haveBRCA1/2mutations that would have a potential impact on clinical trial eligibility and care.

TARGETED ONCOLOGY:Looking back on 2017, what did you find to be the most promising advancement in the field of breast cancer?

Domchek:I am completely bias, because my entire career has been spent looking at genetic susceptibility. But the idea that we can use the reason a person developed cancer, this genetically informed increased risk of cancer, as an Achilles’ heel to target it, and that it is better than chemotherapy, taking a pill and not losing your hair, is actually pretty remarkable.

References:

1. Domchek SM, Postel-Vinay S, Bang Y-J, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD6-11.
2. Robson ME, IM S-A, Senkus E, et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol. 2017;35(suppl 18; abstr LBA4). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.18_suppl.LBA4.