Kathy D. Miller, MD; Lisa A. Carey, MD


June 13, 2011

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Kathy D. Miller, MD: Hello, I'm Kathy Miller, Associate Professor of Medicine in Indiana University School of Medicine, in Indianapolis, Indiana. Welcome to Medscape Oncology Insights on Breast Cancer coming to you from ASCO® 2011 in Chicago. Joining me today is Dr. Lisa Carey, Professor of Medicine in the Department of Hematology and Oncology, at the University of North Carolina, at Chapel Hill. Welcome Lisa.

Several interesting studies are being presented in breast cancer at this year's meeting. Let's start with the one that got the biggest news and perhaps was the biggest disappointment, the phase 3 study of iniparib. So first take us back 2 years ago, when this drug was all the news at the plenary session.

Iniparib: Too Good to Be True

Lisa A. Carey, MD: At ASCO® 2009, the interim analysis of a randomized phase 2 study[1] of iniparib (BSI 201 was its original name), was presented, and it was really a very nice study. It focused on triple-negative breast cancer, which is obviously a subtype of breast cancer for which we don't have any targeted therapies. We're totally reliant on chemotherapy, and there's a big search by a lot of investigators to find targeted agents. This drug was thought to fall into a class of novel therapeutics called PARP [poly ADP-ribose polymerase] inhibitors. It was particularly exciting because the randomized phase 2 study showed a significant improvement in progression-free survival and a significant improvement in overall survival with the addition of iniparib to chemotherapy with no additional toxicity, so it was the win-win of novel therapeutics.

Dr. Miller: It was almost too good to be true. I remember the clamoring that the randomized phase 2 ought to be sufficient to get the drug approved and in use by the time we all got home from the meeting.

Dr. Carey: And it was biologically plausible, right? The idea of PARP inhibitors and triple negative having elements that are similar to BRCA-associated tumors -- and there were emerging data in BRCA-associated breast and ovarian cancer that this class of drugs was going to be important -- you are right, the buzz was huge. The patients, you may remember, participating in these trials were coming out of the woodwork. They would go any place to get into one of these trials. This was the drug with the greatest excitement because it was the only drug with randomized data; it was the only drug that had been tested at that point in triple negative. So I guess now we fast-forward 2 years.

Iniparib in Phase 3: Endpoints Not Met

Dr. Miller: At the insistence of the US Food and Drug Administration, the company did a proper-sized phase 3 study, which must have been one of the most rapidly enrolled phase 3 studies in history. We saw a press release in the usual fashion in January that just said "did not meet primary endpoint." We have now had a chance to look at the data. You've had more chance to dive into the data because you were the discussant for that abstract.

Dr. Carey: Yes. The company changed also, because the drug was developed by a very small company, which was bought by a larger company, and they had always planned to do the phase 3 trial, which was the obvious thing. You are right, that phase 3 trial accrued very rapidly, and the phase 2 trial was published in the New England Journal of Medicine[2] with very positive results. It remained positive, and a week later the press release came out saying that the phase 3 trial had not met its prespecified endpoints.[3] It's not a pendulum thing, particularly, and in truth, the phase 3 simply did not meet the statistical endpoints. There was a numerical advantage to adding the drug to the chemotherapy, but it was not statistically significant, and it wasn't very big.

Dr. Miller: I forget the number but it was tiny.

Dr. Carey: It was not a very big effect. The hazard ratio was 0.79 instead of 0.59; it was a considerably less of an effect. The improvement in progression-free survival and overall survival was no more than a month, so even if it had met statistical significance, there is certainly a decrement in the clinically meaningful element of this, because it's not making much of a difference. We have to accept that. That's the point of phase 3 trials, to be much more definitive and get real data and get a real effect size.

Dr. Miller: We have to accept it, but there is always a desire to try to understand it, or explain it -- whether it's understanding what we got so wrong in the phase 2 trial or what did we learn from the larger trial that might lead us toward an explanation.

Not a PARP Inhibitor

Dr. Carey: You learn a lot from trials regardless of the outcome. First, as we were saying earlier, the nature of iniparib has been a source of some controversy because as more preclinical data have come in, although it has some PARP inhibitory effects, that is probably not how it works in vivo. It does something else and nobody knows what.

Dr. Miller: It's not clear we get to concentrations in the clinic that would really exploit this minor PARP inhibitor activity.

Dr. Carey: No, I mean it's a 1000-fold difference in that kind of activity compared with the other "real" PARP inhibitors. So it does something, because when they look at those gamma-H2AX foci, which are a physiologic readout of DNA damage, they do see that [PARP inhibitor activity] with this drug just as with the other ones, but it doesn't seem to be doing it through PARPs, so exactly how it works is not clear. We have been using this triple negative as surrogate for these molecular subtypes for a number of years now. There is a ton of triple negative clinical trials out there, which ignores the fact that triple negative [breast cancer] is very heterogeneous. It's made up of a whole bunch of subtypes, some of which don't have the biology at all that you are interested in. We probably have to figure out how to get away from just using ER, PR, and HER2 as the drivers. If we're trying to be rational in targeting biologic agents, we're not going to get there with just triple negative or hormone receptor positive or any of these fairly crude [classifications].

Dr. Miller: We did start to see that. They have started to interrogate the tumors that were collected as part of that trial, and by gene expression. I was surprised to see some luminal As and luminal Bs in there that we would think of as being estrogen positive, and wondering what those were doing in there if this was a trial of triple negative patients.

Dr. Carey: Well, they're always in there. The subtyping they presented didn't look quite right. I think they had used a methodology that is not standard, but they will have more reliable subtyping out of that study, and they are fully planning on doing this. But no matter what study and even if you use the best "whatever the gold standard would be" for subtyping, you will always find a mixture; every subtype will show up in there, simply because these clinical assays don't necessarily faithfully represent the biology of the tumor. For example, every population of triple negative tumors I've ever seen anybody do subtyping on always includes about 25% non-basal like breast cancer. We have to acknowledge that misclassification is in every trial that uses this approach.

Back to Square 1 With Iniparib

Dr. Miller: So we have lots of work to do. We have a drug that we don't know exactly how it works, but it does something, both biologically and clinically. We have difficulty identifying patients and subtyping them properly, and still I think there's rational biological enthusiasm for the idea of inhibiting PARP, at least in some patients.

Dr. Carey: Yes. Well, we also have to separate it. There's this drug, which I think once they figure out the mechanism, there may be a totally different approach. It may not be relevant to target basal-like breast cancer for this particular drug. We have to figure out what it does first, so that's the biggest challenge that investigators using that drug really have now.

If you go to actual PARP inhibitors that work through inhibiting PARP, they are still an exciting class of drugs. In the BRCA1 and BRCA2-associated tumors (breast cancer, ovarian cancer) they look like they work as single agents, which is pretty fabulous. Taking the next step into other tumor types and figuring out what other tumor types have functional deficiencies in BRCA1 or BRCA2--that's a challenge that our scientist friends are going to have to help us with, because triple negative don't think is going to get us there.

Breast Cancer Prevention: More Options Available

Dr. Miller: I want to move to a study on the exact opposite end of this spectrum from metastatic disease to prevention. We already have 2 prevention trials, the P1 trial and the STAR [Study of Tamoxifen and Raloxifene], both of which showed benefits to selective estrogen receptor modulators (tamoxifen or raloxifene), yet, in practice, those drugs are rarely used in a preventive setting.

Exemestane Works, but Will Women Use It?

We have now seen the results of the MAP [Mammary Prevention] 3 trial,[4] a very large trial, because all of the prevention trials have been comparing exemestane with placebo. The results, probably not surprising, were that it works.

Dr. Carey: It worked.

Dr. Miller: A reduction in breast cancer, certainly the same or perhaps even better than with the SERMS [Selective Estrogen Receptor Modulators] in postmenopausal women -- a 60% or 63% reduction. Despite the morning news coverage suggesting a complete homerun with this -- and no serious side effects -- I'm not sure that this is an agent women would use.

Dr. Carey: Yes, I have to say we have pretty easy drugs for prevention. Tamoxifen and raloxifene are pretty easy and clearly underutilized. I don't know why the uptake of exemestane would be better in this setting. Unlike tamoxifen, it will be limited to postmenopausal women (as is raloxifene), and you and I both have some familiarity with these drugs.

Dr. Miller: They are commonly used in the treatment setting. Although the toxicities are indeed different, for women who may have been reluctant to use a SERM because of blood clots or endometrial cancer risk, this does not bring those risks, but it brings others, such as concerns about bone loss. What has been underestimated is the day-to-day burden of hot flashes and musculoskeletal toxicity, which, in a preventive setting, has to weigh a bit more on the mind than in a treatment setting.

Dr. Carey: They really didn't report much in the way of musculoskeletal symptoms. They did not capture bone health effectively in that trial[4]; they had self-reporting but not a prospective collection of bone density results. I don't know why there would be fewer musculoskeletal symptoms in the preventive setting than in the adjuvant setting. These drugs certainly do have a side-effect profile that will make them hard for healthy women to take. I'll be interested in seeing how the community at large handles these data and whether people actually start thinking about chemoprevention again.

Dr. Miller: I've become a bit skeptical about reports of musculoskeletal toxicity because in the original treatment trial studies it was reported as 5%-10% and not a big problem. As experience grew (perhaps most importantly as we got better at asking the question and paying attention to patients) musculoskeletal toxicity is substantially higher, so it will be interesting to see if that's the experience in the preventive setting as well.

Dr. Carey: I don't know why the toxicity profile would be different in this setting than in any other, so I expect it will be the same.

Dr. Miller: It is still nice to be able to have an option for postmenopausal patients who have other safety concerns.

Dr. Carey: Of course, none of us knows what the duration would be for these drugs. That's another problem with chemoprevention. All of these trials for the most part use a 5-year duration, as did this one. But what is optimal if you are using it for prevention?

Dr. Miller: Or, what is the optimal timing? You need to be postmenopausal, but do you intervene soon after menopause or at some later point?

Dr. Carey: Right.

Good News for BRCA Mutation Carriers

Dr. Miller: The group that we frequently think about most in need of prevention, would be the BRCA mutation carriers, for whom these may be preventive options, but we are frequently thinking of preventive surgery, particular oophorectomy. There has been at least a theoretical concern that giving those women estrogen might increase their risk for breast cancer and might somehow decrease the preventive effects of surgery. Although we probably will never have perfect data in this respect, we saw the largest study that I've seen from Susan Domchek's group[5] looking at more than 1200 women who had undergone oophorectomy (some of whom elected to take estrogen and some of whom didn't). [The study] didn't find a significant risk [for breast cancer] with using estrogen.

Dr. Carey: Right. That should be reassuring. Those are the kind of data that, hopefully, for these young women who are going to be suffering from the menopausal symptoms of risk-reducing salpingo-oophorectomy can feel relatively comfortable that if there is an effect on breast cancer risk, it can't be very big. Now, obviously this is not randomized; these are observational data, but it's reasonable.

Dr. Miller: Presumably the women who elected estrogen were having the most symptoms and in the most need of relief.

Dr. Carey: It's sort of like the pregnancy story. These are reassuring data for people who have a real clinical need.

Dr. Miller: And important -- as more women get tested and need to consider their prevention options. We have certainly seen a few women tested who were reluctant to consider oophorectomy because of concerns about menopausal symptoms and the thought that they would not be able to take estrogen to alleviate those symptoms if they were particularly severe.

Dr. Carey: That's interesting; then this would help them.

Dr. Miller: It would be nice to be able to give our patients more options and more options with data to support either a big effect or a small effect.

Dr. Carey: I agree. That was a nice body of work and it will be very helpful.

Closing Remarks

Dr. Miller: Thank you, Lisa. Thanks to you our audience for joining us in this edition of Medscape Oncology Insights. This is Kathy Miller at ASCO® 2011.


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