COMMENTARY

OlympiAD: Olaparib Captures Gold for BRCA-Mutated Breast Cancer Patients

Kathy D. Miller, MD; Susan M. Domchek, MD

Disclosures

June 12, 2017

Kathy D. Miller, MD: Hi. I'm Dr Kathy Miller, professor of medicine at the Indiana University School of Medicine, in Indianapolis. Welcome to Medscape Oncology Insights and the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO). At the plenary session this year, we'll be hearing about the OlympiAD trial, which looked at a poly(ADP-ribose) polymerase (PARP) inhibitor in breast cancer patients with deleterious BRCA mutations. We've been waiting for this study for a long time, and here to talk with us about it and provide her perspective on the use of PARP inhibitors in our breast cancer patients is one of the authors of the OlympiAD trial, Dr Susan Domchek.

Susan is professor at the Perelman School of Medicine at the University of Pennsylvania, and executive director of the Basser Center for BRCA at the Abramson Cancer Center, also in Philadelphia. Welcome, Susan.

Susan M. Domchek, MD: Thanks for having me, Kathy.

Synthetic Lethality: How PARP Became Targetable

Dr Miller: Give some background first. Why would we think or hope that PARP inhibitors might be effective in women who have BRCA mutations?

Dr Domchek: It's an interesting story of how understanding basic biology, and understanding how tumors can develop, can lead you to a very interesting and novel type of therapy. When BRCA1 and BRCA2 were first discovered back in '94 and '95, no one really knew what these proteins did in the cell. As we gained understanding, we realized that they helped repair double-stranded breaks in the cell. When you know that, then you could say, how can we figure this out and how could we target it?

In 2005, several teams published studies[1,2] that showed that if you blocked a different type of DNA repair pathway with something called a PARP inhibitor, then you made the cells so unstable that they fell apart. We call that synthetic lethality, with the basic idea that if you block one pathway, the cells can survive. If you block a second pathway only, the cells can survive. But if you block them both, the cells die.

We've gained a lot more understanding about how PARP inhibitors work since then, but that basic understanding holds true. With that information in hand, the next step was to take it to patients who had inherited mutations in BRCA1 and BRCA2 and to see what would happen. In 2009, we had a first readout in a phase 1 trial in the New England Journal of Medicine,[3] showing that these tumors could respond. From there, we've slowly but surely gathered the evidence, culminating in this year, learning about a phase 3 trial[4] comparing one of the PARP inhibitors—olaparib—to standard-of-care chemotherapy in BRCA1/2 carriers with metastatic breast cancer.

Designing the OlympiAD Trial

Dr Miller: These patients all had metastatic disease. Had they had previous chemotherapy or was this their initial treatment?

Dr Domchek: It's an important point. For this particular trial,[4] patients could have up to two lines of prior chemotherapy. There were some patients who had not yet been treated for metastatic disease, but they all had anthracyclines and taxanes at some point before getting the PARP inhibitor versus the standard-of-care chemotherapy.

Dr Miller: Standard-of-care chemotherapy is a little hard to define when you have such a broad patient population; some of them may be receiving their first therapy and some may be receiving their third therapy. How did the trial manage that?

Dr Domchek: This was a point of intense debate, and as you can imagine, whenever you're designing a clinical trial, you cannot let perfect be the enemy of good. We understood that this was a relatively rare patient population. We wanted to make sure that the eligibility criteria were broad enough for patients to be brought into the study and, at the same time, not compromise results by having too heterogeneous of a population.

For this study, the three particular standard-of-care chemotherapies were defined at outset and included capecitabine, vinorelbine, and eribulin as the potential choices. Patients had to have already received a taxane at some point, and that's quite important. We had patients come in having received a variable number of chemotherapies. It's also important to know that patients who had estrogen receptor–positive cancer were also allowed into the study, but they had to have received at least one hormonal therapy in the metastatic setting.

OlympiAD Results: Good Enough for Gold?

Dr Miller: In this comparison, I'm going to guess that olaparib did better, or it wouldn't be at the plenary session. But how much better was this?

Olaparib is not chemotherapy. It's a targeted mechanism. It's oral. Patients don't lose their hair.

Dr Domchek: We've been involved in breast cancer research for a long time, so we have been through the trials and tribulations of different drugs. Some of the things that you want to know are: How much better is it? How toxic is it? Does it have a specific-targeting or a more general chemotherapy effect? I think the particularly interesting thing about this research is that olaparib is not chemotherapy. It's a targeted mechanism. It's oral. Patients don't lose their hair. We already had some advantages compared with standard chemotherapy.

What we see here is that it is better, and the primary endpoint was progression-free survival. The hazard ratio in favor of olaparib is 0.58. In addition, there were fewer grade 3 and 4 toxicities in the olaparib group, and there was an improvement in overall quality of life in the olaparib group. The response rate was twice as high in the olaparib group compared with chemotherapy. All in all, everything's pointing in a really positive direction with this drug.

Dr Miller: You're telling us the oncologic equivalent of light beer really does exist? It tastes great and it's less filling, it worked better, less toxic, better quality of life.

Dr Domchek: Yes.

Dr Miller: What about myelosuppression? Because that has been an issue with some of the PARP inhibitors.

Dr Domchek: One thing that we've learned is that it's very hard to combine PARP inhibitors with chemotherapy, particularly the more potent PARP inhibitors. That's just very hard to do. When olaparib is given as monotherapy, as it was here, anemia was actually more of a problem than neutropenia. These are not drugs that are without toxicity. Nausea, potential vomiting, and anemia are the main things that we're dealing with, but they can be managed by dose interruption and dose reduction. I think it's really important for people to not think of this as being like a sugar pill. No—this is a real therapy, but just like how we figured out capecitabine and how to dose-reduce that and keep people on their therapy, it'll be important to have that understanding here with olaparib.

The Question of Platinum

Dr Miller: One class of chemotherapy that you didn't mention is the platinums, which in some ways takes advantage of the same biologic understanding. But platinum wasn't among the standard-of-care chemotherapies in the trial. Could patients have received previous platinum therapy?

Dr Domchek: Yes. In this particular study, patients could have received platinum in the adjuvant or neoadjuvant setting if at least 12 months had elapsed between then and the start of the study. In addition, they could have had their platinum in the metastatic setting, but their tumors could not have progressed while they were on platinum. The important consideration, which you raised and which is very valid is, should platinum have been one of the arms?

We remind ourselves that platinum is not an approved treatment of metastatic breast cancer. That's not to say that we don't use it, but it's actually not an approved medication. At the time that this study was initiated, although there were some early data regarding platinum use in BRCA1/2 mutation carriers, there was not the level of study that we currently have today. What do we do with that? How do we look at platinum versus PARP inhibitors? Platinums are not nontoxic; particularly with continuous use, people can have significant neuropathies. However, both carboplatin and cisplatin in various studies have shown very high response rates in BRCA1/2 mutation carriers. We have to look at the toxicity issue and we also have to look at this concept of overlapping resistance mechanisms.

What do I mean by that? We know that one of the resistance mechanisms to platinum-based therapies is reversion mutations of BRCA1/2, and that has also been seen to some degree with PARP inhibitors. We don't yet have a full understanding of this intersection of PARP resistance and platinum resistance. We know that there is overlap, but we're not exactly sure about how much overlap there is.

We still have a way to go in figuring out how to use these drugs.

We still have a way to go in figuring out how to use these drugs: platinum, which—let's face it—is cheap, available, but also somewhat toxic, and PARP inhibitors, which are less toxic and more expensive. We want to know the best thing for our patients in the long run, and we still have work to do.

Dr Miller: I was thinking of a very practical question for our listeners who are going to be thinking of treating patients. In the time that this study's been going on, we have gotten more data on the benefit of platinums in patients with no mutations and the potential increases in pathologic complete response in an early-stage setting, by using platinums even in unselected patients with triple-negative disease. If I have someone with a mutation who had platinum as part of her early therapy, and who now has metastatic disease, is that a patient in whom I should be thinking about using a PARP inhibitor? How many patients in the OlympiAD study had had previous platinum? Did that seem to affect the results in that subset?

Dr Domchek: Approximately 20% [of patients in the study had received a platinum], and there was an initial stratification analysis on that basis. We are not necessarily powered to look directly at the subset, but it doesn't look like it's the only answer to this question. I would say, on the basis of the study, [that if patients are] more than a year out from their initial platinum therapy for early-stage breast cancer, it would make sense to use a PARP inhibitor in that setting.

Lessons From Ovarian Studies

Dr Domchek: I think the one place that we have to be careful, which is not informed by this study but which has been suggested by others, particularly ovarian studies, is that when a tumor is truly refractory to platinum, when there's significant progression of disease, and while that patient is still receiving a platinum-based therapy, there does seem to be a much lower response rate than if the individual had received platinum months or years before. Those are things that we need to sort out and work on. But if someone has blown through platinum-based therapy, that may not be the person to immediately put on a PARP inhibitor.

Dr Miller: I think our practitioners are going to have the reverse question as well, because the majority of the patients they see for whom the OlympiAD trial is going to inform their care, have not had a platinum. Most of the patients I know would much rather have a pill that does not cause alopecia or nearly as many side effects as a platinum. If they are not progressing on olaparib and they've never had a platinum, should I consider that maybe platinum doesn't have a role for this patient?

Dr Domchek: I think we don't have all of the information yet. There have been some data from ovarian cancer that show responses in those settings. I think we need to do that post-PARP analysis in more detail, and there will be some secondary analyses that will be exploratory from this study, because we did keep track of what therapies people received after their initial study indicated therapy.

With olaparib you see the response in the same amount of time you see with chemotherapy.

I don't have the exact answer yet, but one thing I wanted to emphasize is that not only were the response rates high in the olaparib arm, but the time to response was the same as in the chemotherapy arm. If you will, as medical oncologists treating breast cancer patients, we think of hormones like: Yes, they're effective, but they may take a little longer to see that response. With olaparib, you see the response in the same amount of time that you see with chemotherapy. That is actually somewhat reassuring: For a BRCA1 triple-negative patient, you don't have to give her chemotherapy upfront necessarily, because we are seeing these high response rates and the same time to response as in the chemotherapy arm.

A Lot to Swallow

Dr Miller: One last practical question about olaparib. The dose was 400 mg twice a day. It comes in 50-mg capsules. I can already hear my patients groaning about 8 capsules twice a day.

Dr Domchek: Yes, the formulation has changed. In this study, it's actually 300 mg twice a day in a tablet formulation as opposed to the capsule formulation. We have made some progress on that; they're 100-mg tablets, so there are fewer pills per day. We still have work to do. The tablets are easier.

Dr Miller: Three tablets twice a day is much easier than eight capsules twice a day.

Dr Domchek: I have had three patients for many years who have been on the olaparib capsules and are choking those capsules down twice a day—for years. We do always have to think of how to make it easier for patients to stay adherent to their medications, and currently, lowering the total number of pills taken each day is part of that picture.

Dr Miller: Susan, thank you for coming in and sharing this really exciting news with us. It's fantastic to see the biology really coming to fruition.

Dr Domchek: Thanks for having me. I appreciate it.

Dr Miller: Thank you for joining us today. This is Kathy Miller, reporting from ASCO 2017.

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