Adam Brufsky, MD, PhD, Medical Oncologist, talks about a drug that brings cholesterol levels to such a low point they are able to prevent some heart diseases.
Can you tell me a little bit about the Olympia trial?
BRUFSKY: Olympia was an interesting study. The idea behind BRCA associated breast cancers is they have defects in DNA repair. So, in other words, the DNA is broken in half. We call it a double-stranded DNA break, and it must be joined together. In BRCA-deficient cancers, you can’t rejoin the DNA. What PARP inhibitors do is they introduce mutations into DNA to induce these double-stranded DNA breaks that can’t be repaired in BRCA-positive cells. PARP inhibitors have been used in ovarian cancer for a long time. There are now trials in prostate cancer and pancreatic cancer that have shown benefit. We had a trial in metastatic breast cancer called Olympiad in which women that were BRCA positive were given a PARP inhibitor, in this case a drug called Olaparib, that provided a benefit. They had a progression-free survival benefit of about probably three or four months. The same thing was repeated with another drug called Talazoparib, in what’s called the Embrace trial. We had a lot of data for metastatic disease. And in breast cancer, when we see things in metastatic disease, we want to bring it forward to earlier stage disease. What they wanted to do in the Olympia trial is take those patients who are BRCA-positive and give them a PARP inhibitor to see if it would prevent recurrence, and it did. The trial was about three to four hundred women, of which a substantial proportion, like 20%, were S receptor positive. But the majority were triple negative breast cancer. The guidelines right now used to be every woman with a triple negative breast cancer under 60 would get BRCA tested for what we call the germ line, so we test it in every cell of their body. We have women now that are BRCA positive, they get chemo, have residual disease, get the drug, and have a survival of like 85% at three years versus 77%. We believe this is probably going to change the standard of care. There was a lot of interesting things too that came out of the trial that we looked at. It turns out one of the things is that, when the women recurred, fewer of them recurred in their brain when they had distant recurrence. That means the drug is probably getting into the brain and preventing brain recurrence, which is good. It gets through the blood-brain barrier. It is very uncommon for drugs to do that, so we’re very excited about that. The other thing that’s interesting, even though it was not a primary endpoint of the trial, is that in the study women looked at second primary cancers and there were fewer. So, it suggests, at least in these women who are BRCA-positive, PARP inhibitors can be potentially preventative. Now, again, it’s only a clue and what we call hypothesis-generating. But the idea is to maybe do a clinical trial of using PARP’s as potential prevention. Now, they do have side effects. So, they’re not benign drugs. We can’t use them like hormone therapies. They do have a few more side effects than that. But on the other hand, it’s pretty exciting stuff.
Why is it important to have something else in the toolbox for people with the BRCA gene and these early cancers?
BRUFSKY: If you come in, we’re going to have a lot of tools and we’re going to figure out which one to use. For example, in triple negative breast cancer, it looks like immune checkpoint inhibitors, like Pembrolizumab or Atezolizumab, seem to have benefit in early clinical trials. It was debatable for a while, but it looks like there’s going to be a progression – disease-free survival benefit – for at least Pembrolizumab and probably for Atezolizumab, eventually. We have those, but we also have PARP inhibitors. So, which one do we give? Do we give both? Right now, we don’t because of the toxicity, so we’re going to end up giving one or the other. We were talking about this yesterday to a few other people, it’s going to depend on which one becomes available, or which one the FDA approves first. We have clinical trials of both, but those are way off.
And this is Lynparza, right?
BRUFSKY: This is Lynparza. Olaparib is Lynparza. Talzenna is Talazoparib. Traditionally, we don’t do PARP tests or BRCA testing on these people unless they have a strong family history. So, should we be testing them without a strong family history? We know 5% of all S receptor positive early stage breast cancer is going to be associated with BRCA mutations. The question is do we test everybody to get that 5%? And assuming they have high-risk disease, do we give them a PARP inhibitor? It’s going to be a really interesting dilemma that we’re going to have. It’s an embarrassment of riches. The problem is that we don’t know, clinically, which one to use right now.
What is the important takeaway from this trial?
BRUFSKY: If you have a family history of breast cancer, and it’s significant enough, you should tell your doctor about it because you should be tested. There are potential drugs that will help your breast cancer. That’s the real takeaway and getting a BRCA test.
Could you describe a PARP inhibitor and how it works?
BRUFSKY: A PARP inhibitor is a pill taken once or twice a day. Lynparza is two pills, twice a day. Talzen is one pill a day. These are PARP inhibitors that are commercially available for breast cancer. And again, they’re pills, and they’re given daily. The major side effects include anemia, a little bit of low white blood count occasionally, and nausea. Those are the big ones.
Would the next step be waiting on FDA approval?
BRUFSKY: Yes. The FDA’s going to look at the data. This trial was a registrational trial, which means the FDA will look at it for approval. It’s going to be a label expansion because it’s already approved for other indications.
Is there anything you’d like to add that you want people to know?
BRUFSKY: The big takeaway is to ask your doctor now about BRCA testing. I think the breast cancer community — advocates, doctors, other health care providers, funders like the Department of Defense and NIH – are really going to take a close look at how often we should be doing BRCA testing. I think that’s the big issue. The other issue with BRCA testing is that it will help us therapeutically for when we have a BRCA mutation in your family, and what to do with that? Do other people want to know? Does your daughter want to know? Do your sisters want to know? And what will they do with that information? We have a shortage of genetic counselors in this country. That’s a bigger problem. We’re going to always have people who have these BRCA mutations because we’re doing them to see what therapy to give, but then what do we do with their families? One of the roadblocks to getting widespread acceptance of this is what do we do with your family if you happen to be BRCA positive.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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