乌鸦传媒

PARP inhibitors have emerged as important new therapies for breast cancer patients who have an inherited BRCA mutation. Use of these agents in the neoadjuvant setting was the focus of two major abstracts presented at the recent virtual .

In this first of four exclusive episodes, 乌鸦传媒 brought together three expert leaders in the field -- moderator , of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, is joined by , of the University of Texas MD Anderson Cancer Center in Houston, and , of Northwestern Medicine Feinberg School of Medicine in Chicago -- for a virtual roundtable discussion about the and trials.

Following is a transcript of their remarks:

Rugo: Hello. I'm Hope Rugo, a professor of medicine and director of Breast Oncology in Clinical Trials Education at the University of California San Francisco's Comprehensive Cancer Center. We are going to talk about some interesting updates from ASCO 2021. With me today are my excellent colleagues, very knowledgeable and key opinion leaders in breast cancer. Dr. Jennifer Litton is professor of medicine and vice president of clinical research at MD Anderson's Comprehensive Cancer Center, and Dr. Bill Gradishar, who is professor of medicine and chief of hematology-oncology at Northwestern University. Both of my colleagues are experienced clinical trialists and clinicians who specialize in breast cancer.

We are going to start this conversation and talk about two really important trials that were presented at ASCO this year. One trial in particular is practice-changing today, but I think the other trial also has significant implications for the way we treat a specific population of patients with early-stage breast cancer.

These trials are OlympiA and NEOTALA. Really, Jennifer Litton started the whole investigation of PARP inhibitors as neoadjuvant therapy for patients with BRCA1 and BRCA2 mutations. Jennifer, tell us a little bit about the OlympiA trial and NEOTALA.

Litton: The OlympiA trial was an international, phase III, randomized controlled trial of over 1,800 patients. Everyone had to have a germline BRCA1 or BRCA2 mutation. The eligibility really looked at whether they had chemotherapy upfront or surgery upfront, or if they were hormone receptor positive or triple-negative breast cancer.

Basically, they had to be considered high risk with very specific definitions such as triple-negative breast cancer, node-positive, or greater than two centimeters, or had any residual disease after neoadjuvant chemotherapy and surgery. In the hormone receptor-positive, if you had greater than four lymph nodes at the time of surgery, or if you had neoadjuvant chemotherapy and had significant residual disease.

Really, the endpoint is invasive disease-free survival. This study was stopped based on the fact that it was a very positive trial. At 3 years, the invasive disease-free survival was 77.1% versus 85.9% for the patients who were given 1 year of adjuvant olaparib [Lynparza] therapy.

The 3-year distant disease-free survival increased from 80.4% to 87.5%. Given these findings for patients with high-risk early breast cancer in a germline BRCA, PARP inhibitors in the adjuvant setting are now, I consider, a standard of care. I think it will have a lot of implications for how we look at giving these drugs to these patients and also who we consider for genetic testing and rethinking our genetic-testing guidelines.

The NEOTALA study was a study that started off as just a 2-month window study at our institution. We gave 2 months of single-agent talazoparib [Talzenna] -- it's a once-a-day pill -- and what we found was that we were having a dramatic and early response to the PARP inhibitor in decrease in tumor volume, at least for all-comer germline BRCA1 and BRCA2.

Given that response, instead of going on to then chemotherapy and surgery, we changed the study ... to 6 months of single-agent talazoparib, taking them to surgery, and there were 20 patients, 19 of which were evaluable in a pilot study at our institution with a 53% rate of pCR [pathologic complete response]. Now, that included both ER [estrogen receptor]-positive and triple-negative.

The NEOTALA study -- this is the multicenter-sponsored trial -- looked at pretty much the same design and started off mostly as triple-negative breast cancer patients, and in fact the entire cohort was patients with triple-negative breast cancer.

The study was initially designed to be a single-arm, phase II study of approximately 120 patients. Just due to the decisions made -- not based on efficacy or toxicity -- but during the early part of the trial, the sponsor decided to truncate this study to 61 patients. We reported that the pCR rate by independent central review for the evaluable [patients] was 45.8% and in the intention-to-treat [group] was 49.2%.

When we look at toxicity of both of these trials, we definitely see what we know for the PARP inhibitors: increased anemia in the NEOTALA -- that was 39.3% -- had Grade 3 anemia -- and patients did require dose-reduction delays and blood transfusions in 13 of the patients.

Rugo: That's some really interesting data, Jennifer, and indeed in the OlympiA trial as well, about 5% of patients had at least one transfusion. The majority of patients had transfusion. But the other side effects like nausea and headaches seemed to be fairly modest, mostly Grade 1 and 2, and more than 90% of people were able to complete the whole year. It definitely suggests that overall it's pretty tolerable.

Now, Bill, I think the questions that have come up are a number: One is would you give this now to all patients who have a BRCA1 or BRCA2 mutation? Or would you limit it to the OlympiA-like population? If you do limit it, thinking about the toxicity and cost, then what do you do with the other treatments like capecitabine [Xeloda] and potentially the CDK4/6 inhibitor abemaciclib [Verzenio]?

Gradishar: At the present time I think that I would be more inclined to follow the eligibility that were in the OlympiA trial. I think the data from the trial are pretty compelling, and I agree it's practice-changing. ASCO has already adopted that as part of the practice guidelines and, as you know, the NCCN [National Comprehensive Cancer Network] voted on that. I think that this will be incorporated very quickly.

Now, should it be administered or recommended to every single patient, even with the very small, lower-risk tumors? I'm not sure that I'm willing to make that leap yet. I would be interested what Jen thinks about that.

Litton: Sure. I would follow at this point the eligibility. For me, when I'm thinking about the CDK inhibitor or capecitabine, although these are not cross-trial comparisons, nor will we ever likely get to those, I think given the impact of this data I would choose for my patients to go right to a PARP inhibitor versus the CDK inhibitor or capecitabine for triple-negative at this time.

Rugo: Yeah, I would too. I think that you could, for example, sequence the abemaciclib. I'm happy to get rid of capecitabine in these patients because, based on the ECOG data, it doesn't seem as though it's doing such a great a job, at least in our population of patients who tolerate a lower dose than potentially our Asian colleagues. I think that it makes sense to use this in the triple-negative group and to sequence the CDK4/6 inhibitor after PARP inhibitor in patients at very high risk -- for example, stage III disease, etc.

There is also the question of ... Well, before we talk about that one, because there are two questions I still want to get to, one is what's the future of PARP inhibitors as neoadjuvant therapy? I mean it looks like if you had a stage II triple-negative cancer and you could take 6 months of olaparib or talazoparib, that seems like it will be a lot better than getting ACT [doxorubicin (Adriamycin), cyclophosphamide, and paclitaxel (Taxol)] with carboplatin [Paraplatin] and pembrolizumab [Keytruda].

Litton: No, I agree. I think it really evolved because we were listening to our patients. The idea of taking a pill once a day, not being in an infusion center for 3 hours a week, getting weekly paclitaxel, was really appealing to them. It's not without toxicity and I don't want to portray it as such.

But I think this would be a very reasonable de-escalation strategy, because it still leaves all the other options on the table -- polychemotherapy, everything -- after the fact as well.

I think that it's going to be some really, hopefully intriguing, looks as we start to try to figure out who those progressors were. I'm really also intrigued by the anemia. In my clinical experience when we see this, it's a lot of patients do very well and don't need significant dose delays or dose reductions.

But in the early stage, which I saw much more than in the metastatic and BRCA stage, where we see these patients treatment-naive and their hemoglobin is 12, and 3 weeks later it's 6, trying to understand it's really a precipitous drop for some of these patients.

This is something I think we need a lot more investigation into, is this some other biomarker that we can look to? I certainly have some ideas on that, that we are looking into to try to pre-identify those patients who are going to get those grade 3 anemia.

Rugo: That's a really interesting idea, because then potentially you can even use the erythropoietin-type approach, since we don't think it makes breast cancer cells grow. Now, that would be interesting to see.

But I think then the question is how long you treat for, and what the outcome is. That's why the 60 patients are tough, but hopefully some of the neoadjuvant trials like will be able to incorporate this data as a de-escalation strategy or a personalization strategy.

Then, Bill, the last question is really would you be screening now for somatic mutations in the early-stage setting in high-risk patients? Or we get PALB2. I don't see it much, though. I have to say it's pretty uncommon relative to BRCA mutations. But would you use olaparib in high-risk patients in that population?

Gradishar: For somatic mutations, I don't think the data applies directly to that. I think the broader question that has gone unsaid at this point is -- at least today; I know it was discussed when the data was presented -- is who should we be screening? I think they legitimately flipped the question to say who shouldn't we be screening for these mutations. Because I think that now we have a tool -- meaning a drug -- that is applicable, whether it's in the neoadjuvant setting or the adjuvant setting, we have to know who the patients are, who are potential candidates. But I don't think that I would apply, for instance, the OlympiA data to somatic mutations.

Rugo: What about, Jennifer, for PALB2?

Litton: We don't have clinical trial data per se in the setting for PALB2. We have to extrapolate from other data that we see in multiple other studies in the metastatic setting showing that PALB2 appears to be very sensitive to PARP inhibition and DDR [DNA damage repair] inhibitors, just similar to BRCA2. I don't think we'll ever see a PALB2-only study that will have any numbers to be very meaningful.

I would certainly promote that when we consider these trials from now on, we should consider them for a germline BRCA1, BRCA2, PALB2 with subsets for somatic too. We certainly have data showing that for several somatic mutations there is also susceptibility to these strategies.

Rugo: But if you had a patient in your chair today who is 34, had bilateral mastectomies with residual triple-negative breast cancer after neoadjuvant therapy, and has PALB2 germline mutation, would you recommend olaparib?

Litton: Biologically, I think it should absolutely fall in line with OlympiA. Will we get it and get it approved, and be able to have it covered?

Rugo: That's another question.

Litton: But that's a very ... am I going to ask a patient to spend that amount of money? That is an important thing to do. Do I think it would fall in line with OlympiA? I would suspect it absolutely would.

Rugo: Right.

This has been a fascinating discussion and really exciting information, which I hope will continue to stimulate work in the neoadjuvant setting. Certainly, patients who have BRCA1 and BRCA2 mutations in breast cancer have been waiting for this data for decades. It's very exciting to see it come into clinical practice.

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