Chemotherapy and PARP Inhibitors in BC


Joyce A. O’Shaughnessy, MD: Thank you very much for that discussion on ER-positive early-stage disease. Our final segment is on triple-negative breast cancer. Hope, there have been some new data that you presented from CALGB 40502, and some data on dose-dense therapy in the adjuvant setting. Should we all be using that exclusively?

Hope S. Rugo, MD: In neoadjuvant therapy, too. Yes. We presented an updated analysis of CALGB 40502 as well as a subset—an unplanned look at additional subsets in terms of evaluating the relationship between being treated with nab-paclitaxel versus paclitaxel, or ixabepilone versus paclitaxel as weekly chemotherapy—3 weeks on, 1 week off—in combination with bevacizumab as first-line chemotherapy for metastatic breast cancer.

When we looked at the subset analysis and did a multifactorial analysis, there appeared to be a relationship in the triple-negative population with treatment with nab-paclitaxel. Whether it was so, there was a suggestion that nab-paclitaxel was potentially a better treatment option. Again, they are just hypothesis-generating data. They weren’t done prospectively to answer that question. The other complication in CALGB 40502 is that the dose of nab-paclitaxel is 150 mg/m2. The majority of patients had dose-reduced fairly quickly because that’s not really a tolerable dose, except in a phase II trial that was done in Russia where it was tolerable. That was used to decide on our dosing.

Even though everybody dose-reduced, we still saw that question of a benefit in patients with triple-negative disease. There also were some data from the GeparSepto trial that suggested that nab-paclitaxel was potentially superior in pathologic complete response rate and in longer-term outcomes in patients who had triple-negative breast cancer.

So, those are kind of interesting data, but they are not definitive. I don’t know if we’ll ever know if nab-paclitaxel, at a specific dose, is superior. At the same time that the GeparSepto data were made available, in terms of PCR rates, there was another study done in Italy that recently published, which looked at nab-paclitaxel as a 3-week on, 1-week off schedule. Results showed no difference in pathologic response. Although nab-paclitaxel is preferable in some patients who have neuropathy or allergic reactions to paclitaxel, we just don’t know enough about differential efficacy.

The early breast cancer trials group did a huge meta-analysis looking at 21,000 women in 16 randomized trials. That was presented in San Antonio. They looked at dose-dense versus non—dose dense chemotherapy regimens and found that dose-dense was better. It didn’t matter whether you had hormone receptor–positive or hormone receptor–negative disease. Remember, that’s not centrally determined, right? The way it all works in meta-analyses and in these trials shows that there are some data, which isn’t for sure. But dose-dense therapy was safe and it works better. Patients who had better outcomes received dose-dense therapy.

Dose-dense is quite different. Paclitaxel given every 3 weeks was less effective than dose-dense paclitaxel. But it’s not true for every drug. Memorial Sloan Kettering Cancer Center looked at giving dose-dense docetaxel. It may be more toxic, and too toxic to give to patients. It’s not really a reason to give everything in a dose-dense manner, but dose sensitivity seemed to be better.

Joyce A. O’Shaughnessy, MD: That’s good. That’s a nice advance. That’s a definite advance in the adjuvant setting. In the triple-negative metastatic setting, for our BRCA1/2 germline patients, how are you incorporating PARP inhibitors into the metastatic setting? Is it safe to maybe combine this with a checkpoint inhibitor?

Sara A. Hurvitz, MD: The data we have right now is from 2 phase III clinical trials in the metastatic setting. Both studies limited their trial participation to BRCA1 and BRCA2 mutation carriers in both triple-negative and hormone receptor-positive disease. Although we’re all eager to see the activity of PARP inhibitors in triple-negative breast cancer that is not associated with the BRCA mutation, we don’t have that data yet. The OlympiAD study and the EMBRACA trial looked at olaparib or talazoparib, respectively, versus treatment of physician’s choice, which was single-agent chemotherapy. Both studies showed a 3-month improvement in median progression-free survival associated with the PARP inhibitor.

Olaparib has now been FDA approved, so it’s available to us to use. It’s a great tool to have in our toolbox for patients with metastatic germline-associated breast cancer.

Talazoparib is not yet available outside of a clinical trial. The question of how to improve the progression-free survival, as Hope alluded to earlier, received really good response in patients. It was very exciting and very satisfying, but it doesn’t last for a very long time—less than a year. There are some patients who do have prolonged durable responses, but it’s a minority of patients. So, can we combine it with low-dose chemotherapy, other pathway inhibitors, and immunotherapy, which is a very hot area right now?

In San Antonio, Susan Domchek presented an abstract looking at durvalumab with a PARP inhibitor in patients with BRCA1/2 mutations. There were about 25 patients in that analysis. About 8 patients who had confirmed responses, and an additional 5 had unconfirmed responses. The tolerability, importantly, was good. There were some cytopenias, but there was nothing out of the ordinary of what we would see with single-agent therapy. I think there are a number of ongoing studies looking at that combination strategy.

Joyce A. O’Shaughnessy, MD: That’s very exciting in the metastatic setting.

Hope S. Rugo, MD: Durvalumab and olaparib are being tested in the neoadjuvant study, along with paclitaxel. You want to think of it like it wouldn’t work because it’s been demonstrated that you have too much count suppression in the metastatic setting. But if you give a lower dose of the olaparib, you can actually deliver it. This is now an arm that just opened in our I-SPY neoadjuvant phase II trial. It will be interesting to see this. Of course, there are other studies going on that are looking at combining a PARP inhibitor with a checkpoint inhibitor, and then something else.

Joyce A. O’Shaughnessy, MD: At the ASCO Annual Meeting, Jennifer Litton showed preoperative talazoparib in the BRCA1/2 germline population, which was highly active, etc. That’s very exciting in that group. And, of course, we think about the OlympiA study in the adjuvant setting. We really need these results of that big time… Right?

Debu Tripathy, MD: There’s a lot of interest now in profiling patients. We have a lot of tools available. Whether or not that’s all going to pan out, it helps us select patients to test to see if a strategy might work. The intelligently-designed trials that have all this built in are going to be the most informative. Fortunately, most of them are doing that, especially in the neoadjuvant setting. And so, hopefully we will discover phenotypes that actually lend themselves to unique combinations, whether it’s EMT inhibitors, or PARP inhibitors, or immunotherapy. So many of these trials are ongoing. The problem is that they’re all so small. What we need are larger trials to get a good look at this.

Joyce A. O’Shaughnessy, MD: Yes, but at least we can get some of the phenotypes identified.

Transcript Edited for Clarity

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