In this episode Dr. Slavin welcomes Dr. Judy Garber, Professor of Medicine at Harvard Medical School, Chief of Division of Cancer Genetics and Prevention at the Dana Farber Institute, and Susan F. Smith Chair. Together, they discuss the OlympiA study and outcomes that have influenced industry guidelines.
0:00:11.7 Thomas Slavin: Hi, I'm Dr. Thomas Slavin, Chief Medical Officer for Myriad Genetics. Welcome to Inside The Genome. Hi everyone, welcome back to the podcast. Today, we're delighted to have Dr. Judy Garber, she is the Susan F. Smith chair, and chief of the Division for Cancer Genetics and Prevention at the Dana-Farber Institute. She is also a professor of medicine at Harvard Medical School. Thank you for coming on the podcast today, Dr. Garber.
0:00:38.9 Judy Garber: Thanks for having me, TJ.
0:00:41.4 TS: I wanted to have you tell the audience a bit about yourself, what you do, for those that don't know you. However, you're incredibly famous in the hereditary cancer world, so everyone should know you. [chuckle] I also wanted to bring you on to go through OlympiA, which was a ground-breaking study that recently came out. And so for those that want a reference, this is a title of the publication, which is in the New England Journal in 2021. It's, "Adjuvant Olaparib for Patients with BRCA1 or BRCA2 Mutated Breast Cancer". So thank you so much for coming on, telling people a little bit about yourself, so they get to know what an academic physician scientist does with their time. And then some of the amazing work that you're doing here, really advancing the field for germline mutation carriers and PARP inhibitors.
0:01:29.0 TS: So to that end, if you wanna give a little bit of background of how did you end up becoming who you are and doing what you're doing. If you wanna tell a little bit about your back story, 'cause you're not a medical geneticist, however, many people would think you are, with your comfort level with the BRCA1 and 2, hereditary gene mutations and all of your other knowledge base.
0:01:51.0 JG: Okay, I'll try. So I am a breast medical oncologist and I do clinical cancer genetics. My research background is in epidemiology. I'm old enough that when we started doing cancer genetics, it was mostly recognizing that there were cancer families. And I was interested in breast cancer and just at the time that I was finishing my fellowship, BRCA1 was mapped and TP53 was identified as the Li-Fraumeni gene, so it's that far back. And then, with the molecular explosion, and then it was possible to characterize people as having mutations in specific genes or not, or pathogenic variants, as we'd say today, and who did and who didn't? And which families were and weren't. So then, suddenly it was important to be able to distinguish people.
0:02:41.7 JG: And once it was understood what BRCA1 and BRCA2 did, which was not immediately obvious from those days when the gene was found. But once it was recognized that they were important in repairing DNA errors, then it became reasonable to think, "Well, maybe, they could be treated differently, or maybe they should be managed differently otherwise, maybe they can be prevented differently." Then there was a lot to think about.
0:03:11.6 TS: And how did you end up doing what you're doing at Dana-Farber and Harvard?
0:03:15.4 JG: Well, I was very lucky, because when I was resident at the Brigham and Women's Hospital, we rotated at Dana-Farber, and I learned about Fred Lee, who was from Li-Fraumeni Syndrome. So, when I did my fellowship there, there was an opportunity to study with Fred and train with him, in the same way that other people were doing lab work, which is probably the biggest hole in my career, that I never did that, but working with Fred, I learned how to think about cancer genetics, or at least cancer families. And so, then I just stayed [chuckle] and fortunately for me, the Farber became a good home for people like David Livingston who worked on BRCA1, Alan D'Andrea, people who were... Richard Kolodner was there then, he worked in Lynch syndrome genes, although really, Richard is a yeast geneticist, and they just figured out that the genes he was studying, were important for Lynch syndrome.
0:04:11.9 JG: So it was just a great time. Even Steve Frank was there in those days, he had just discovered RB. So, it was a good time to think with those people, and in the way that the best work is collaborative, there was that. And then the rest of those collaborations were from people at other places, places you've been, Ken Offit, with Mark Robson, with Barbara Weber and in those days with Susan Domchek, with Jeff Whitesell, they were then... Then everybody working together, you could expand the range of what you could work on.
0:04:44.2 TS: Yeah, no, that's great. And you've done a lot of clinical research. Are you seeing patients right now?
0:04:52.0 JG: I do see patients. I see breast cancer patients one morning a week, and I see genetics patients two afternoons every week. It's helpful, it lets you remember what the important questions are for the patients.
0:05:02.8 TS: Yeah, absolutely. You kinda touched on a little bit, I mean, where we're going with the treatment and how to really take care of individuals with hereditary cancer mutations. I asked you to come on and talk about, a little bit about OlympiA just because, really, just again, such a ground-breaking study. Do you wanna explain a little bit about, kind of, the concept of the study and where it originated from and tell people a little bit about the study?
0:05:29.7 JG: I'd be glad to. I would just say first that, the PARP inhibitors were fascinating drugs that Alan Ashworth and others began to work on, with a small company, so this is a good... For me, my only foray into drug development... Lots of people do more than I do. But it was clear from the early data that these were drugs that might work, almost exclusively at that time, in people who had inherited mutations in BRCA1 and 2, so their tumors would have lost both copies of one or the other gene. And then in those days, we were only really thinking about breast and ovarian cancer, we didn't think so much about pancreas or prostate, 'cause we hadn't yet really demonstrated how important these were.
0:06:15.7 JG: And in the early studies, there were signs that these would work, but there were also some real missteps, like the first big study was with a drug that turned out not to be a PARP inhibitor and though the drug... Its first trial looked positive, the BIG trial was negative and it was almost the end of the whole field. But it finally prevailed upon the Pharma, the drug companies, to come back and try these trials, and they first thought there wouldn't be enough mutation carriers to be interested. Like all drug development, the work began with people with advanced disease, metastatic disease. And so first in ovarian and then in breast, you could show that these drugs, at least could have a response, and then, as is always done in cancer drug development, it began to move earlier and earlier.
0:07:04.4 JG: So the important trials like EMBRACA and OlympiA, that showed that if you gave a PARP inhibitor to a woman with metastatic breast cancer, when she first became metastatic, before she'd had much other treatment and compared those women getting a single-agent PARP inhibitor to a chemotherapy drug, except Platinum, you could show that their drugs were active and that women did better and did better longer. And that encouraged moving the drug ever sooner, so you'd have a chance to improve the chances for cure, and that's where OlympiA came from. There had already been studies like this in ovarian cancer, because, I think, there were fewer alternatives for women with ovarian cancer. Here in breast cancer, took a while to get there, but then finally, here was the opportunity for OlympiA.
0:07:57.0 TS: Yeah. And look it, ovarian cancer that, it has been incredible. To see the progression-free survival, that's now going on with bringing in PARP inhibitors into a maintenance phased, or adjuvant chemotherapy for individuals with ovarian cancer. Just really a game changer in itself for the field and... Yeah, it's exciting to see now this work spilling over to breast. And yeah, as you've mentioned, prostate, pancreatic, a lot of these, BRCA1 and 2 pre-disposition type cancers. And what did you... And how was the study set up and what were the findings?
0:08:35.8 JG: So the study was set up in a slightly unusual way. So this was an international collaboration, which seemed necessary to collect 1836 BRCA1 and 2 mutation carriers in...
0:08:48.6 TS: And this is in OlympiA, I should preface.
0:08:53.1 JG: OlympiA study. So we knew we would need a large number of patients, and the trial was first conceived, I think by the... Some large clinical trialist groups, the BIG and... The Breast International Group in Europe, and the NRG and Alliance in the United States. But they had to get support from pharma, so they had to get AstraZeneca, who makes Olaparib to agree to help support the study. But the study was done... I say it's unusual, because usually there's one protocol, everybody's got the same thing. And here, although it was one protocol, part of the study was run by BIG, part was run in the United States. They put all the data together in one place, but they were not exactly the same, and it was considered not exactly AstraZeneca's trial, but a collaborative effort. I don't know whether pharma will ever do it again.
0:09:44.8 JG: But actually, it worked quite well. And Frontier Science kept the data, and it became possible to do this. Now, AstraZeneca had to agree that they would help screen patients to look for their BRCA mutations, because not everywhere in the world is it easy to get screening done. So that was a big investment from Europe too.
0:10:04.8 TS: And what were the findings, when you put people either on PARP inhibitor or a placebo, after their original chemotherapy? And actually, I have a question even before that. I've always been confused personally on the selection criteria for the patients. It wasn't done off of regular staging that we tend to think of, like all stage two or stage three patients, or all people with chemotherapy. There seemed to be some very specific selection criteria. I was just wondering personally, how that came about and the thought process of that, and then how people were enrolled?
0:10:45.6 JG: I think it's an important question to have always, "Who is in the study?" So the study was partly figured out by who had high risk of recurrence, because otherwise, who needed to get extra treatment at the end of all the other treatments? So, for triple negative patients, it was a little bit easier, people who had stage-two or three disease, and where triple negative had a pretty high likelihood of recurrence, even after standard treatment, and that treatment could be either neoadjuvant or adjuvant, and that... Neoadjuvant, meaning before surgery, or adjuvant, after surgery. And that was important because the patterns of care were changing around the world. But If you limited the study to triple negative patients, it would only be BRCA1 pretty much, or mostly. So we wanted to include people with estrogen receptor positive tumors.
0:11:38.7 JG: Well, for that, the FDA felt strongly that they had to have especially high risk, because they were already gonna get chemo and hormonal therapy, and did they really need the risk of anything extra? So they wanted patients who had at least four positive lymph nodes. So now you've got kinda different groups but what they had in common was they had a germline mutation in BRCA1 or 2, and they had a high risk of recurrence, whether they were ER-negative or ER-positive. That's how it came to be those groups. And the randomization was one-to-one, you either got the PARP inhibitor or you got a placebo, and it's blinded of course, no one knew which was which.
0:12:20.7 JG: And it had to be for people who finished all their treatment, not just their chemo, they had to have finished their surgery and their radiation and everything, so they were done, and then they were randomized. And if they had hormone receptor positive disease, they could take their hormonal therapy at the same time.
0:12:38.0 TS: Yeah. And were you surprised by the results when they were un-blinded?
0:12:42.4 JG: I think we were surprised because they were so positive so quickly. This was, it didn't... It only took two and a half years of average follow-up. It took years of getting everybody to that point, but we were gratified, I would say, and happy eventually, that there's something that looked like it could be of benefit and that you could see it so fast.
0:13:04.3 TS: Yeah. And how do you think this is changing practice now? I mean, how've you seen personally or heard from colleagues?
0:13:11.1 JG: I think we were impressed that, because there was a different... Now remember, we haven't shown that people live longer from having this treatment, what we have shown is that they were less likely to have their disease come back very quickly, and especially for triple-negative breast cancers, which we all know can recur very quickly. This was helpful, and it was enough of a difference that it became part of guidelines from ASCO immediately.
0:13:36.5 TS: Yeah, very quickly. Yeah, I was surprised.
0:13:37.6 JG: They clearly wanted this to become part of care. In the US, where we largely have access to new treatments right away, this has certainly changed care, people are going on to the drug. I think in parts of the world where that's not true, it's gonna take longer and that's been an issue, for trying to do an ethical and culturally sensitive large clinical trial, you'd hate to show a benefit in countries where people then can't get the treatment, so that's an issue. But in the US and in other parts of the world, this has now become part of treatment, and we now have to think about this, actually in places I didn't necessarily anticipate, because at the same time, we were being shown that immunotherapy was helpful for triple-negative...
0:14:26.6 JG: And what do you do now when you have a [0:14:28.2] ____? It gives the triple negative... You give the Olaparib. What about the immunotherapy? So people are really trying to move quickly to adjust, to progress in both areas. Isn't that great? What a nice problem to have.
0:14:41.3 TS: [laughter] Yeah, exactly, yeah. And where do you see this all going? Right now, the guidelines that came out from ASCO, and NCCN breast treatment also updated, I also saw that the NCCN and Hereditary Breast and Ovarian Cancer Committee now have taken OlympiA inclusion criteria at least as something that should be considered for anyone undergoing germline mutation testing. Where do you see the whole field moving over time? How are you talking with patients about it now?
0:15:16.2 JG: I think there are probably a couple of... Maybe let's say three major impact places, one of course is who's getting genetic testing. So, with results in metastatic disease, showing that PARP inhibitors were a good thing when people have mutations, now, you had to test women with metastatic disease, and men to see if they were eligible if you hadn't already done it. So, that was a game-changer. Now you're saying we have to know a diagnosis to someone have a recO mutation or not, because if they do, we should consider them. Now, that means, as NCCN says, "If they would be eligible for treatment", so people who have a recO mutation and a tiny tumor who would not be eligible, maybe they wouldn't need to know, but for people whose care would change, then we have to figure out how to do more testing up front.
0:16:07.5 JG: That was a big impact. The second impact was saying, "Well, great, now we have a drug that works, but we were only giving it after a lot of other treatment. Maybe we could give it instead of some of that treatment", so I think you're gonna see clinical trials coming forward asking, "When should we use the PARP inhibitor?" Give somewhat less chemo and give PARP inhibitor instead. And even what about patients with smaller tumors, or patients with even ER positive tumors were pretty determined to keep those ER positive tumors in the mix, but to add the PARP inhibitor, could be used earlier in their care and as part of their care instead of chemotherapy, because it does have less toxicity.
0:16:49.7 TS: Yeah. So potentially in the mix for really anyone that may need chemotherapy?
0:16:54.6 JG: I guess, I...
0:16:54.7 TS: Then maybe, as in place of chemotherapy at some point, yeah.
0:16:57.0 JG: Right. First, I think some... The other question that's...
0:17:01.3 TS: Clearly need more studies, but... Yeah, yeah.
0:17:03.1 JG: Yeah, these are all clinical trials, you can't just say, "Okay, now we can use this." But I think with more follow-up, if we're able to show that people do live longer and that the drugs are safe. Because there was remarkably no important difference in toxicity on the people who took the Olaparib and the one who didn't. If that's true, then people are starting to ask, "Can we use Olaparib or other PARP inhibitors for prevention?" Now that would be a change.
0:17:30.3 TS: Yeah. And some of that data may come out of this work, I don't know if that's been... I thought it was being looked at, I don't... You probably have better insight than me, but in the sense of reduction in second breast cancers.
0:17:46.2 JG: So, people are certainly asking about second cancers, I think for second breast cancers, it might be a challenge because many people, as you know, who find out they have a mutation have bilateral mastectomy, they don't wait for a second tumor, so it may be hard to show second breast cancers, it may just not have the power, you might be able to show less ovarian cancer if people have put off that surgery, and then there may be other cancers too that are prevented by the medication. For the breast cancer, for primary prevention, could you use this drug? I don't think you could take this every day for years on end, not for your bone marrow, but you might be able to take it for a month a year, or [0:18:29.2] ____ month.
0:18:29.2 JG: That sort of thinking is very different for prevention, but it becomes possible with this kind of data, and to me, that's one of the... If that really came to be, that would be a huge transformation.
0:18:40.9 TS: Yeah, that would be absolutely incredible. That was a great overview of the study, and for those out there that haven't looked this over, because as I am talking with people around the country, a lot of people know about it, but I have been surprised that some people have not heard of it yet, so yes, if those of you who are listening, if you have not seen this study, please go take a look. And then I just wanna ask, anything that you're working on now that beyond maybe OlympiA that you wanted to tell people, or let people know where your work is going yourself.
0:19:13.0 JG: Well, thanks for that opportunity, I will give a little...
0:19:14.7 TS: Kinda just putting this on you.
0:19:16.8 JG: Yeah, well, no there's... We're gonna have to wait to figure out more about how to do prevention with a PARP inhibitor, but there is another trial that's gonna open in the US that is already open in Austria, Australia, Spain and Israel, and will also open in the UK, and Germany. So just in case you have an international audience for this and you never know.
0:19:41.9 TS: Yeah, we do actually, yeah.
0:19:42.9 JG: I bet you do, but this is the BRCA-P trial. This is just is another prevention trial for women with BRCA mutations, BRCA1 in particular, who have not had breast cancer and have not had surgery and are willing to take the drug denosumab. Denosumab is a drug used to treat osteoporosis. So it's been proven to be healthy in women without cancer. It is used in cancer patients to protect their bones too, but this trial compares that to a placebo in women who have some time before their planning prophylactic surgery to see if we can actually prevent breast cancer with this drug, and while it's not obvious to anybody, where did this come from?
0:20:22.1 JG: There's data in both mice and humans, that this drug, which block a molecule called RANK ligand, so this is a RANK ligand inhibitor and it can prevent breast cancer in mice with BRCA1 mutations, so this is a study that's gonna be opening the US in early 2022 and is open elsewhere in the world, and certainly if people are interested, we'd love to tell them about the trial, so keep an eye, the study will start to be advertised, I would say the first part of 2022, and is a really important effort, something that we hope will make a difference for the next generation in particular.
0:21:01.0 TS: Yeah, no, that's fantastic. How many people are you looking to recruit for this?
0:21:05.5 JG: Well, the study overall will be bigger than OlympiA.
0:21:10.1 TS: Yeah.
0:21:10.7 JG: 100 women in the US, about 300.
0:21:12.4 TS: Yeah, no, that's great. Well, thank you for all you are doing, no, this is huge. And again, I really appreciate you coming on the podcast today. Yeah, you are clearly an expert in this field and moving the needle for a lot of people that otherwise wouldn't have access to these kind of life-changing treatments, so you're doing a lot. Well, more than just seeing your own patient population, you're really moving things for the entire world, so also hats off to your collaborators through all this work, it takes a village, and you just hit on that with the last study, BRCA-P, because you can't do it alone and you need a lot of sites to help recruit a lot of patients, and you need a pharma companies and testing companies, and a lot goes into all of these trials.
0:22:02.7 JG: Well, I should just say that the OlympiA trial would not have been possible without a huge network of collaborators, and I should not in any way make it down like I did this study. This was an enormous international effort. Myriad was actually the testing lab, the central lab for the study and tested about 25,000 women to find the people on the trial. The patients really get a huge credit. It's an incredibly brave thing to be part of a trial when you have a scary disease and diagnosis, and we should never underestimate what that takes, but it's very exciting to be able to work together on things that you hope will make a difference, and certainly not everything does, so it's a thrill when something looks like it can offer better futures. That's what it's all about.
0:22:52.3 TS: Yeah, yeah. Well, keep doing what you're doing. Thank you so much for coming on.
0:22:57.1 JG: Thank you.