Olaparib Shows 'Unbelievable' Response Rate in MBC With PALB2 or BRCA Mutations

— Expanded trial data confirm potentially practice-changing results


At the American Society of Clinical Oncology (ASCO) annual meeting, updated data on the use of olaparib (Lynparza) in patients with metastatic breast cancer (MBC) with somatic BRCA1/2 and germline PALB2 mutations corroborated the remarkable results seen in the initial trial with these specific patients. The findings could potentially change clinical practice, especially in the metastatic and high-risk adjuvant settings.

app brought together three expert leaders in the field for a roundtable discussion: moderator Hope S. Rugo, MD, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, is joined by Joyce O'Shaughnessy, MD, of Baylor University Medical Center and Texas Oncology in Dallas, and Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in Boston. This final of four exclusive episodes focuses on the from the Olaparib Expanded trial.

Click here to watch the other videos from this ASCO roundtable series on breast cancer.

Following is a transcript of their remarks:

Rugo: In the new mini-orals for metastatic disease, we saw a really cool study. I mean, I'm really happy to see this result. The mini-orals, again, replacing the poster discussions and giving this sort of supposed soundbite. But actually they were very good in-depth presentations; I thought a lot of interesting data.

So, just to pick out this one that I think has the most practice-changing potential was presented by Nadine Tung and she had done an original trial called Olaparib Expanded, just looking at patients who had somatic mutations in BRCA1/2, germline PALB2 mutations, and then other mutations that are associated with DNA repair defects like ATM, CHEK, etc. They didn't have a whole lot of patients in the original paper, which was . But it showed remarkable data, very small numbers in patients. Great response in PALB2. I mean, I think it convinced all of us that PALB2 should be treated as a BRCA2, but it's not in the approval for that. And so people still struggle a little bit. And then for the somatic mutations, lower response, but still very impressive somatic mutations of BRCA1/2.

So in this presentation she did a further expansion to try and get a little bit more power to look at those two groups -- germline PALB2, somatic BRCA1/2 -- because there were no responses in these other mutations, ATM, CHEK2, etc. So Joyce, tell us a little bit about that.

O'Shaughnessy: Very, very nice looking data. It basically corroborated her initial findings really quite well. And was it about 60 patients with germline PALB2 that were treated and standard olaparib...

Rugo: About 30 patients.

O'Shaughnessy: ...about 30 patients, yes. And it was a 75% response rate.

Rugo: Unbelievable.

Shaughnessy: Yeah, very, very nice looking waterfall plot, really it's a home run, it's a major home run. And then the somatic BRCA1/2 patients, it was a 37% response rate. And I looked at... you look at the waterfall plot, it looked to my eye, it looked like BRCA2 was a little more than BRCA1, not statistically significantly so, but the BRCA2s looked like they did a little bit better.

And durability. Durability was there too about a year-ish, maybe a little longer. So very, very nice. And not really dependent on the allele fraction of the BRCA1 or BRCA2. They couldn't really say that you could pick out a group that would not benefit from given a somatic BRCA1/2 mutation.

So I really hope that the PALB2 data will be practice-changing both in the metastatic setting and in the high-risk adjuvant setting, the patients that were eligible for the OlympiA.

Rugo: Absolutely.

O'Shaughnessy: So really, practice-changing data. I think so.

Rugo: Yeah, it was interesting, the somatic BRCA2 and BRCA1, it seemed like you were more likely to have a response if you hadn't gotten chemo before, which I think is just what we see with everything. The less-heavily pretreated, the better it is. And chemo really drives out those resistant clones. But with the somatic BRCA, there was also some association, although very small numbers with ER [estrogen receptor] and triple-negative, which you wouldn't see as much with PALB2. And I thought that was quite interesting. The triple-negative patients seemed to have a better response than the hormone receptor-positive. And also there was some association with the type of mutation with deletions being, in the small number of patients with deleted BRCA, that they seem to have really phenomenal response. So would you now use that, as you probably already have, but would you use that as standard of care?

Tolaney: I was going to say maybe I'm a little biased. That study was at our institution and so after we saw the initial data, because Nadine's initial presentation had very similar data, it was like a 50% response in somatic BRCA and about 80% in germline PALB2 in that original presentation. And as you noted, these numbers are not that different. And so I think this validates that. But we did start prescribing olaparib in these two patient populations in the metastatic setting once we had seen those data. And I agree, while OlympiA obviously is a very different setting, in the adjuvant setting, I think if you did have a patient who had a germline PALB2, in addition to having a germline BRCA mutation, we would offer olaparib.

I don't personally do testing on tumor in the early-stage setting, so I don't actually know if they would have a somatic BRCA alteration, if I knew that maybe I would offer it.

Rugo: I don't even think we know how frequent it is. It certainly doesn't come up as one of the most frequent mutations. I mean we've seen quite a lot of NGS [next-generation sequencing] in early-stage disease and it doesn't pop up, so it may be acquired.

Tolaney: It does seem like at our institution, one of our colleagues had looked at prevalence of somatic BRCA and it did seem to be even more prevalent in a post-CDK [cyclin-dependent kinase] setting. We were seeing as high as 10% in the metastatic ER-positive setting post-CDK in later lines. So maybe there is some difference there.

Rugo: And particularly in lobular cancer, which is often hard to manage and keeps changing over the time, they have a higher incidence of all of these kinds of somatic mutations. So I think it's really exciting. And of course we'd already incorporated it as well. We participated in that first study. But this data I thought was really quite definitive in terms of including the patients with germline PALB2 mutations in the OlympiA-like population, which we also already had been doing. And then the metastatic of course, where we're looking for things. Would you also give olaparib in the OlympiA-like setting?

O'Shaughnessy: Yes. Yeah. And I've done it once or twice already and I've been able to get it, a little bit of legwork to get it. But these are high-risk ladies who were eligible for OlympiA. These are high-risk women. So yeah, I do think it's important.

Rugo: That's great. Well, I mean, we've talked about four studies, some not immediately applicable to the clinic, but in the not-too-distant future. Really remarkable to have so much exciting information at ASCO this year, and really nice to be able to discuss it in real time to talk about how we interpret this data. I mean, that's one of the really exciting things about being at the meeting with our colleagues is that opportunity.

Of course, there was a lot of other data at ASCO we don't have time to talk about now, but these I think were the most important ones to really address immediately in the immediate time. I really appreciate your time and your thoughts in this roundtable.

Tolaney: Thank you so much.

O'Shaughnessy: Thanks, Hope.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.