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Behind the Breakthroughs: A Promising New Therapy for High-Risk Breast Cancers

Dr. Susan Domchek breaks down results from the game-changing OlympiA trial

Among the biggest headlines out of this year’s American Society of Clinical Oncology annual meeting were the results from the phase III OlympiA trial involving more than 1,800 patients with early-stage HER2-negative breast cancer who had a high risk of recurrence and carried inherited mutations in the BRCA1 and 2 genes.

OlympiA researchers (including several BCRF investigators) reported that patients who received the PARP inhibitor olaparib (Lynparza®) after standard-of-care treatment experienced a significant reduction in local recurrence, metastatic recurrence, and death compared to the placebo. The results of this trial could have wide-ranging implications, especially for people diagnosed with triple-negative breast cancer—a form of the disease that lacks many targeted treatments and is most common in BRCA1 and 2 gene mutation carriers.

RELATED: Notable Updates in Breast Cancer Research from ASCO's 2021 Meeting

BCRF’s Margaret Flowers, PhD spoke with Dr. Susan Domchek, one of the OlympiA’s co-authors and a member of our Scientific Advisory Board, about the study’s highlights and what happens next. Watch the full video above or read the edited version of the interview that follows.

Tell us about yourself and your research.

I’ve been a BCRF investigator for 10 years now. BCRF has been a tremendous asset to get research done and to look for the newest and most innovative areas to work. I’m a medical oncologist with a specialization in genetics, so I see individuals who have mutations in genes, such as BRCA1 and BRCA2, and an increased risk of developing cancers. Over the years, what we’ve learned is that not only does information about an individual’s inherited genetics help determine what cancer risk they have, but also helps us figure out exactly how to treat them. And, as you’ll hear, this particular study is a great example of that fact—and a major step forward in our field.

This trial, OlympiA, involved a class of drugs called PARP inhibitors. How do they work and why were these patients are good candidates?

When BRCA1 and BRCA2 were first discovered, we didn’t really know much about how they functioned in the cell. But we did know that if you had a mutation—also known as a pathogenic variant—in one of these genes, you had an increased risk of cancer. As our basic science colleagues figured out exactly how these schemes work, we figured out that if you have an inherited gene mutation like BRCA1, that means that most of the time your tumor does not have BRCA1 protein present and actively working. That matters because BRCA1 and BRCA2 are helpful. We all have BRCA1 and 2 genes, and those proteins help repair DNA damage. Tumors that don’t have functional BRCA1 or BRCA2 don’t repair DNA damage correctly. So early on, we couldn’t think of a way to target a protein that’s turned off. Most of the things that we target in cancer [like estrogen and HER2] are turned on.

So extremely clever people, including BCRF investigator Dr. Alan Ashworth, figured out that you could use PARP inhibitors, which themselves inhibit a different type of DNA repair pathway. If you repair one DNA repair pathway, like BRCA1-related DNA, the cell can live. If you inhibit a different type of DNA repair pathway, like PARP inhibitors do, the cell can live. But, if you inhibit both pathways, the cell can’t live. It’s too much, and it dies. Olaparib is the PARP inhibitor we’ll talk about today. Talazoparib is also another one that’s relevant to breast cancer. Both were previously FDA approved for metastatic breast cancer based on the OlympiAD and EMBRACA trials [both which were also conducted by BCRF investigators].

What did the OlympiA trial find?

OlympiA enrolled individuals who had BRCA1 or 2 mutations, and those that were at high risk for their cancer coming back. There were individuals with triple-negative breast cancer whose tumors were over two centimeters or had positive lymph nodes, as well as individuals who had had preoperative chemotherapy and had cancer left. There were people with ER-positive tumors that had either four positive lymph nodes or quite a bit of cancer left after chemotherapy. These women and men were randomly assigned either olaparib or a placebo pill after their regular treatment. There were more than 1,800 patients in this trial, which is a testament to the power of collaborative and international research, and BCRF investigators from all over were part of it.

What was amazing is that the women and men who received olaparib were much less likely to get their cancer back, including outside their breast (metastatic disease). This is a really big advance. We don’t yet have data to show that it makes people live longer, but that’s just because we haven’t had long enough follow-up time. It is trending in that direction. The other important thing is quality of life. We saw that although there are side effects with olaparib, individuals’ quality of life was really pretty good. And lastly, there were no big changes in other areas. For instance, we don’t see, at least at this point, an excess risk of leukemia or other cancers. This really is a game-changer for individuals who have BRCA1 or 2 mutations and have high-risk, early-stage cancers.

Is this available to patients now? What’s next?

At the current time, there is not FDA approval for the use of olaparib in this adjuvant [after treatment] setting. That is planned. But this is different from the question of if you can give the drug at this point. Off-label use occurs in oncology. So far, even though my numbers are small, I have been able to have insurance cover this drug, and I do think that the data are compelling enough that oncologists should be trying.

I want to be clear though that this drug is not for everyone. Even BRCA1 and 2 mutation carriers can have very early-stage cancers or estrogen receptor–positive cancers that are small and lymph node–negative. This drug does have side effects, so not everybody—and not every BRCA1 and 2 mutation carrier—should get this medication. We need to be thoughtful about weighing risks and benefits. But the group that was included in the trial—those particularly high-risk patients—yes, I think that they should get the medication.

Does this study change how we think about genetic testing?

Everybody who has triple-negative breast cancer should get genetic testing. And the reason why is that 85 percent of the time, BRCA1 mutation–related breast cancers are triple-negative. Individuals with triple-negative breast cancer are much more likely to have a BRCA1, BRCA2, or PALB2 mutation. And even though PALB2 wasn’t directly tested in this study, these drugs likely work in those cases as well.

Estrogen receptor (ER)–positive cancers are different, and I want to be clear that if you are a 70-year-old woman with a lymph node–negative, ER-positive cancer, olaparib is probably not a good addition, whether you have a BRCA1 or 2 mutation or not. A 70-year-old woman with an ER-positive tumor who is not of Jewish descent and has no family history is exceedingly unlikely to have BRCA1 or 2 mutations. We’re not going to be giving olaparib to everybody. But individuals with very high-risk ER-positive breast cancers might get genetic testing to determine the therapeutic benefit of olaparib.

Do we have a sense yet of how many people this will impact?

We don’t know the exact answer yet because we don’t have the survival benefit. But distant disease–free survival tracks pretty well with eventual overall survival. I think this is going to be most impactful for triple-negative breast cancer patients, and again, that’s not to say that there’s no benefit in ER-positive patients, but we have fewer treatment options for triple-negative breast cancer. The idea of having something that can change outcomes by that much is huge, and 75 percent of the patients in this study were triple-negative. About 10 to 15 percent of patients with triple-negative breast cancers have BRCA1 or 2 mutations, depending on a person’s age. So that’s not nothing—that is a good chunk. These tend to be young women; the median age in this study was in the 40s.

I’d like to just add something we know through BCRF investigators, but we must keep making clear: We have a disparity in genetic testing in this country, where white, well-educated women in a higher socioeconomic class are much more likely to get genetic testing than underrepresented minorities and individuals in a lower socioeconomic class. We need to make sure that we are testing every person with triple-negative breast cancer, but that’s not happening. Just like every ovarian cancer patient should get tested. So, if the new therapeutics like this one drives testing—because we cannot deprive these individuals of potentially lifesaving medication—then that’s great. That gap just absolutely must close.

Read the rest of BCRF's coverage of the 2021 ASCO annual meeting here.

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