Case 4: Chemotherapy or PARP inhibitors for BRCA+ TNBC

Hope Rugo, MD, FASCO: It’s fascinating—that first-line data—and I think it is motivating to all of us, even though it’s a small subset of those patients and there may be some biases. How do you decide when you want to use a chemotherapy induction versus a PARP inhibitor first, Adam?

Adam Brufsky, MD, PhD: In a way, BROCADE 3 speaks to that. My idea is a single agent PARP for now. In the absence of the BROCADE 3 data, I would say to give the single-agent PARP and not do the chemotherapy induction like they do in ovarian cancer. But I think that as we’re going to find out in a minute while talking about the BROCADE 3 data, people’s minds may change.

Hope Rugo, MD, FASCO: That’s interesting. And then, of course, there are other trials as well. Before we move on, you generally manage anemia by reducing the dose. Has there ever been a situation where you’ve changed from one PARP inhibitor to the other, Ian?

Ian Krop, MD, PhD: To me, it was always striking. I think Adam alluded to the fact that from an efficacy standpoint, the drugs look so superimposable—olaparib versus talazoparib. You know, exactly the same hazard ratio for PFS [progression-free survival] and almost the exact same response rate. But they do seem to differ a little bit. It does seem like there’s a bit more hematologic toxicity with talazoparib. If you have a patient who’s on talazoparib who’s having anemia that is a significant problem, you may potentially switch. For most patients I tend to use olaparib, so it hasn’t come up. On the other hand, if someone’s responding to a drug, that makes you worry a little bit about switching.

Hope Rugo, MD, FASCO: Yes, although they do seem to be so similar. I have only switched in 1 patient due to nausea, but I think that it’s hard to know. There does seem to be a bit of differential toxicity, so there is a consideration for dose reducing. As you mentioned, Adam, there are a lot of new directions in using PARP inhibitors for breast cancer, in both the metastatic setting with a chemotherapy induction type of approach and in the early-stage setting, as well as combinations with immunotherapy. Do you want to talk about those a little bit?

Adam Brufsky, MD, PhD: Again, I think there are a lot of really interesting things. In particular, where to put the PARP inhibitor in the therapy itself. We remember that our ovarian colleagues would give chemotherapy first to a maximum response and then add the PARP as maintenance. There are survival benefits associated with that approach. It’s never really been done in breast cancer, but at least we can get some hints on this from the BROCADE 3 trial. This was a trial where women had less than 2 prior lines of therapy, less than 2 prior lines of platinum, and were randomized in a 2:1 fashion to veliparib, carboplatin, and paclitaxel or a placebo, carboplatin, and paclitaxel. And you could crossover to veliparib with progression.

Again, the primary endpoint was PFS [progression-free survival]. I personally would have used restricted means analysis, but they used PFS and there was a PFS benefit. The reason I would have used restrictive means analysis is because if you look very carefully at the curves, you see they’re separated at about month 8 or month 10. That’s a month or 2 after stopping the chemotherapy. To me, it suggests that you’re not really getting a lot of benefit from the combination.

I think people could argue differently, but the curves really seem to separate when you have the maintenance of olaparib versus a placebo. I think that’s a really important subtlety here. Hopefully, I think, we understand this a bit and argue whether or not it’s true. This may argue for using chemotherapy first and then PARP second. But again, the adverse events were kind of what you’d expect. The mean exposure to the carboplatin and paclitaxel looks like it was 12 months or 12 cycles—however that was defined—so people in both arms of the trial tend to get the same amount of therapy on study.

At this point, 40% were on monotherapy versus 34% on a therapy with placebo. That seems to be where the curves seemed to separate. It’s after getting chemotherapy for 8 to 10 months and then having that separation that you really see it could be the maintenance like our ovarian cancer colleagues have been seeing for many, many years with these agents. That may be where all the efficacy is. This is just talking a little bit about some other options that are on the table and are being considered.

MEDIOLA was a trial of olaparib with durvalumab in BRCA-mutated breast cancer. Again, you had a run-in with olaparib. The idea was that you drive up some of these DNA repair issues in the cell and get a lot of new neoantigens presented. Then you would get durvalumab to have that immune effect. It looked kind of interesting. Hopefully we’ll take that on a little bit further into phase 3 clinical trials.

A variety of phase 3 clinical trials in early-stage breast cancer are going on.

There is the OlympiA trial, which is studying maintenance treatment in high-risk disease. A lot of the high-risk disease tended to be in women who had neoadjuvant chemotherapy and had residual disease. I had a number of women on this trial in that exact setting.

The partner study is similar to what we’re saying—olaparib with carboplatin and paclitaxel versus carboplatin and paclitaxel alone. This is a trial that’s very interesting. And then, you can see there are a lot of neoadjuvant trials. There are trials of rucaparib with radiation.

And finally, there was a trial that I’m really fascinated by. This is a trial of single-agent talazoparib. I believe it’s just about closed. Twenty patients were trialed with talazoparib as a single agent for 4 to 6 months and then all went to surgery. Chemotherapy was given after at the investigator’s discretion.

It turns out that the pathological complete response rate [pCR] was around 50%. Another 10% or 11% of patients actually hit RCB [residual cancer burden]-1, which is a pretty good prognosis. So this is really fascinating. And it was interesting that the original trial design was 111 patients, but they stopped at 70 for some reason. I’m really curious as to why they stopped the study.

Hope Rugo, MD, FASCO: My understanding is that their plan was to try and actually do a randomized trial to get a better understanding of who benefits. So there were plans to do another study after this larger confirmatory single-arm study, which is interesting.

Also, there is a metastatic trial that’s looking at patients who’ve gotten an induction with gemcitabine/carboplatin/pembrolizumab and then are randomized to receive either continued chemotherapy and pembrolizumab, stopping therapy as needed for toxicity, versus pembrolizumab/olaparib as a combination regimen.

There are really a huge number of studies. Even MEDIOLA and other trials are looking at treatment in patients with HRD [homologous recombination deficiency] defect, etc. So we’re going to see a lot of data in this area in the near future. And with our registration trials ongoing, that will help us to understand the benefit of combining these agents—I-O [immuno-oncology] and PARP inhibitors—in the future. Of course, we’re very excited about seeing the data from OlympiA, eventually.

I think now we’ll wrap up our very interesting discussion. We’ve talked about a number of different cases and really covered all the big areas in breast cancer. I’m sure we left some critical areas out, but we talked about HER2-positive disease. We’ve talked about hormone receptor–positive metastatic breast cancer. We talked about metastatic triple-negative disease. And then we talked about what to do in patients who have BRCA germline mutations, with considerations for using PARP inhibitors.

I’d like to thank our panel for your thoughtful case presentations and for this lively and informative discussion. And in particular, I’d like to thank Dr Evita Sadimin for joining us from the pathology side to give us an interesting perspective as well.

To our viewing audience, thank you for joining us for this Targeted Oncology Virtual Tumor Board® presentation. We hope today’s discussion was a valuable use of your time, and we hope that you were able to acquire some practical knowledge that you can take back to your clinic. Thanks very much.

Transcript edited for clarity.