 For adding targeted agents, it appears that for the 

, PI3 kinase mutation inhibitors, like alpelisib and the other agents that were treated before, the toxicity can be a major issue. Understanding the time course helps us a lot in managing it. What’s interesting is that both hyperglycemia and rash for alpelisib peak in the first 2 weeks after administration, whereas diarrhea can be a long-term toxicity. Knowing this helps us a lot in terms of prevention.

We just published this data in from the SOLAR-1 data set. What we would have recommended is that patients have a hemoglobin A1C [glycated hemoglobin] at the end of fasting glucose before they start alpelisib. It’s really important to understand what their risk factor is. We know that patients have certain risk factors and we’re going to see more about that in further analyses of SOLAR-1.

One known risk factor is a hemoglobin A1C that is not within the normal range, which means that a patient will experience hyperglycemia during their course of treatment with alpelisib, so you need to check the glucose at day 8 and day 15. Every week for the first 2 weeks is really important.

Just telling somebody to eat low carbohydrates is really hard for patients, and you need a really low-carbohydrate diet. Another thing that people have done is to use prophylactic glucose. I think the newer agents may be better. You know, the ones that are advertised on the television all the time, but they’re SGLT2 inhibitors and are hard to get.

I am hopeful that we’ll be able to design an intervention for patients that’s prophylactic and helps in managing the hyperglycemia. They definitely need diet counseling as well. You already mentioned that prophylaxis for rash with a nonsedating antihistamine works incredibly well. They’re both issues, and you want to advise people of the risk of diarrhea and different diets, making sure they have antidiarrheal therapy around.

 Thanks, Hope. That’s fabulous. I want to hear from Denise and Tiffany. Are there any particular management strategies—things you’ve observed or your experiences?

 One of major things we learned early on with everolimus, adding the mTOR inhibitor, is that when we are combining a partner with endocrine therapy, it really is much different from the days of endocrine therapy monotherapy, in which a prescription was rendered and the patient was given a prolonged follow-up. We didn’t need lab evaluation for an aromatase inhibitor or tamoxifen or fulvestrant. A lot of those patients weren’t coming back intermittently for labs or checkups or phone calls from the nurses or even return appointments that were on a short scale.

What we’ve learned and what our practices are continuing to do is a lot of patient education. We do want to hear about things that patients are experiencing when they leave our clinic, and this may be very different from their adjutant experience with endocrine therapy with these new partners. I know from my practice, when I’m talking to a patient and they’re relieved that it’s not a chemotherapy recommendation that I’m giving for hormone receptor–positive patients.

I very quickly tell them that you can have a lot of different toxicities, so it is not the stereotype that many of the patients either from adjutant therapy have experience in terms of chemotherapy. These endocrine partners, these biologic targeted agents—hitting these key pivotal pathways—have a whole host of different but serious adverse effects that we can manage. But we need to intervene early.

We need to check on these patients and do a lot of the education and bring them back for visits, which was never what I did with endocrine monotherapy. Now we’re like, “We need you to come back. We need you to do a check for CBC [complete blood count]. We need you to…look at the patient’s RAP [right atrial pressure].”

Part of it is managing toxicities that we clearly want to be adept at. The other key part is if we don’t manage these toxicities, we’re not going to get compliance, and those patients are going to be out there and self-discontinue and not make us aware, and I think that’s the key. I do that lecture up front with the patient. We may have some bumps in the road until we get the right dosing, the right combination of medications, to support you through this partnership, but it’s pivotally important because it’s in compliance for you to gain and derive that benefit or a chance at that benefit.

We’ve got to do our best to make you able to tolerate any of the toxicities that come along, so you can be an equal partner in doing your part, in being able to manage the compliance aspect when you walk out of the door. It’s a lot more education for myself when I’m face to face with the patient, as well as for the staff when they’re answering those phone calls. These are different times when a patient is on an endocrine combination backbone therapy vs endocrine monotherapy.

Certainly, some of the nurses were like, “Oh, you want this to PCP.” I’m like, “No, I want that patient in our office.” But they’re used to it, and it’s a lot of education just trying to break that habit and practice patterns.

 Yeah, it’s really a change. It’s a complete change. It’s so important though, as you say. Tiffany, what has been your experience? Many patients with weight loss, a need for dose reduction. Patient selection?

 The key about education in managing expectations is that it can’t be overemphasized. Being sure our patients are aware of what to call about. Being sure they’re aware of diet and glucose monitoring. The rash, in my experience, has been easily mitigated with the use of the prophylactic antihistamines. What I feel like I’m learning is how to be an endocrinologist, how to manage and monitor blood sugars, and how to educate about that. To your point, being sure that our nurses are informed because they’re doing a lot of this frontline work as well and responding to our patients and really keeping them safe at home.

Mitigating these adverse events is important. For me, it’s a learning curve, as it is with many of our new drugs when they enter into our armamentarium. We’ve become cardio oncologists, and now we’re becoming endocrinologists or at least becoming familiar with blood glucose management.

 Thank you. I just want to reiterate what Hope said about patient selection. I tried to cheat a little and have the hemoglobin A1C be 6.5 g/dL or above. It just doesn’t work. People got way too much in the way of hyperglycemia. I think they had tried that in the SOLAR-1. It didn’t work, which is why they said less than 6.5%. It just really has to be that way, taking the time to get their glucose into good control really has to happen. Otherwise it just won’t work.

Then I max out metformin, first as they get their blood glucose above 160 g/dL. I’m monitoring them closely. The home glucose monitors are very inexpensive and easy to do. Write it down, take it a few times a day. As Hope said, it’s just the first few weeks you have to do it. I do go to the SGLT2 inhibitors because they lower insulin; anything that lowers insulin is going to help alpelisib work better and longer.

That’s low carb, the low sugar, and exercise. Basically, metformin lowers insulin, and SGLT lowers insulin inhibitors. I’ve been able to manage it, as I said. I have had some patients who need a dose reduction for excessive weight loss, but then it stopped. Now they’re able to just sail along. I must say, I’ve been impressed with the level of activity.

 It’s interesting too, and you commented on this. What has happened early when people don’t have experience is that they give the patient alpelisib, and then they come back 2 weeks later and they get ketoacidosis and hyperglycemia. Having these proactive approaches is really important. I actually think that what we probably should be doing is prophylaxing in patients, in some way or another, who have these slightly elevated hemoglobin A1Cs.

You can take 2 weeks to better control somebody’s glucose and talk to them about diet and management before you even start. They don’t have to come in at day 8, but you have to check. Having an endocrinologist on speed dial helps a lot with e-consults and things like that; that helps. I find that they generally take a little less of an aggressive approach, but the other thing that’s really important is that if you hold the alpelisib, these pills have a short half-life unlike say tamoxifen.

The hyperglycemia goes away with the flick of an eye, so now you have to be really careful because if you have them on a long-acting hypoglycemic agent, you can cause severe hypoglycemia. You want to stop everything within 24 hours that you’ve been doing if a patient didn’t need it before.

 Yeah, that’s super. It’s good if somebody gets really high on their glucose. Just stop it, and in 36 hours, they’re back down to normal.

Videos

HER2+ MBC Adverse-Event Management

 I want to ask Denise and Tiffany. First, I’ll say that we got the 

, and that’s 40% of our ER [estrogen receptor]–positive patients. Upstream from 

 is mutated in only a tiny fraction of ER-positive patients, but it is part of that whole signaling from a whole bunch of receptor tyrosine kinases that can drive resistance to endocrine therapy. It’s been the target of several trials going on with capivasertib and ipatasertib, 2 AK inhibitors.

We saw randomized phase 2 data and the FAKTION trial looking at unselected patients, ER-positive patients with breast cancer who had progressed on an aromatase inhibitor. Prior to the CDK4/6 availability, fulvestrant plus or minus the capivasertib, and we saw very nice improvement in progression-free survival, regardless of 

-mutation status. That’s in the CAPItello-291 larger phase 3 trial. We’ll have to stay tuned, but it’s a very nice trial for our patients. The AKT inhibition may be coming for certain patients, but we still have everolimus in our practice.

I want to hear from Tiffany and Denise. How are you utilizing everolimus in your practice now. Tiffany, how are you using it?

 Similar to what you had said earlier, we need to understand what the PI3 kinase status is of our patients with hormone receptor–positive advanced breast cancer. That is something that, through cell-free DNA or tissue sampling, we understand. For my patients who are progressing on a CDK4/6 inhibitor who failed to have a biomarker to predict benefit from alpelisib, I still consider the combination of aromatase inhibitor and everolimus.

It tends to be a bit later in my sequencing, but I’ve found it to be much better tolerated with the help of the SWITCH study and the use of oral topical steroids to help reduce the mucositis. I still find it as a tool in my armamentarium, particularly now in those patients who failed to have the 

 I really echo what Tiffany says. I still use it, but not as frequently in the past when that was the only targeted endocrine therapy doublet out there, prior to the CDK4/6 inhibitors. It has moved to a later line, but when I think about where these patients are with their disease struggles and what my choices are to treat if they don’t have a 

 kinase mutation. I can’t think about adding an agent to an endocrine partner. I look at everolimus and feel very comfortable managing that combination.

Addressing dexamethasone and SWISH and the potential of the stomatitis and mucositis in those patients, at every juncture we look at what that progression looks like in that particular patient and the status of their disease in multiple disease sites. The thought continues to be trying to prolong their treatment on therapy endocrine partner, which has been the main signaling of hormone receptor–positive breast cancers, before I move onto sequential single-agent chemotherapies. That’s definitely integrated in that sense.

I still think the driver for many of the hormone receptor–positive diseases after metastatic disease states, after CDK4/6, is still best addressed by an endocrine therapy backbone partner. But eventually those patients slide into the need for cytotoxic chemotherapy. I tried to delay that as long as possible and use all other tools available.

After Progression on PIK3CAi Therapy: MTOR Inhibition

 I want to transition to something we can definitely use after progression on CDK4/6, and that is alpelisib. First, we’ve got to find the right patient population. I’ll say a few words about looking for and finding the patients with the 

 mutation in their breast cancer. Then we’re going to turn it over to you, Hope, to update us on your really nice data, the BYLieve data, from ASCO [American Society of Clinical Oncology Annual Meeting].

This is put against the need for NGS [next-generation sequencing], as Denise said, on the map. We’ve got to find these patients with ER [estrogen receptor]–positive, 

 [human epidermal growth factor receptor 2]–negative metastatic breast cancer, whose breast cancers have a 

 mutation. You know it’s a truncal mutation that happens very early in the development of primary breast cancer.

By and large, if you look for it in the primary breast cancer, you’ll find it in about 40% or so of patients. In the metastatic setting you should find it, and about 40% of patients. Many of us biopsy the first recurrence. Sometimes we don’t get that much tissue. It’s not that easy to assay for NGS all our metastatic biopsies. Here we have our patients; they’re on a CDK4/6 inhibitor, and we need to be thinking about what the next step is for those patients.

And we need to see if alpelisib is going to be an option, so many of us will get ctDNA [circulating tumor DNA] on those patients either upon their initial presentation with metastatic disease or upon progression on a CDK4/6 inhibitor. In data from the SOLAR-1 trial, which was fulvestrant plus or minus the alpelisib, only 6% had a prior CDK4/6 inhibitor, hence the larger experience that Hope found from the BYLieve trial. We found in the SOLAR-1 that patients in the metastatic setting, in whom circulating tumor DNA identified the 

 mutation, did marvelously well with very large separation in the progression-free survival curve. That was very impressive. If we do find 

 mutations in ctDNA in our metastatic patients, that’s a great patient for alpelisib.

If we don’t find it in the circulating tumor DNA, I certainly go back to the patients’ primary breast cancer, and I test it there as well. The NCCN [National Comprehensive Cancer Network] really does recommend that particular algorithm. If I don’t find it in either place, I will check for it again further down the road in the metastatic setting because the PALOMA-3 trial—which gave fulvestrant plus or minus palbociclib—got ctDNA before treatment and upon progression found about 10% more patients had to PIK3CA mutation upon progression on a CDK 4/6 inhibitor.

I’ll keep looking because over time, as Hope said, they’ll be more clonal heterogeneity that evolves, and you might still be able to help the patient. It’s been pretty easy to find the patients with the 

 mutations. Hope, what do we do with those patients who are progressing on CDK4/6 inhibitors? Tell us about the BYLieve data that will help us understand who will benefit from alpelisib.

 These are really fascinating data. Alpelisib was first approved based on the data from SOLAR-1 where patients who had progressed on an aromatase inhibitor had to receive fulvestrant and were either placebo or alpelisib, and then the 

-mutant cohort. The median progression-free survival was almost doubled with a hazard ratio of 0.65, leading to regulatory approval of alpelisib.

The big issue is that SOLAR-1 was enrolled completely before CDK4/6 inhibitors were really approved in most places. We really didn’t have enough data to know how alpelisib would work in this situation; 20 patients in SOLAR-1 had prior CDK4/6 inhibitor treatment. In that group with 

 mutations, the median progression-free survival went from 1.8 to 5.5 months, in such a tiny group of patients.

We designed the BYLieve trial with the idea to really treat those patients. At ASCO we presented cohort A; there were 3 cohorts. The third cohort after chemotherapy is still accruing. The second cohort hasn’t reached the 6-month landmark. In the cohort we presented, patients had to have progressed on a CDK4/6 inhibitor and an aromatase inhibitor as their immediate prior treatment.

Then they were all treated with alpelisib and fulvestrant. They all had to have a 

-positive disease. Our final analysis of these data included patients who also had central confirmation of 

 mutations. Of 127 patients, 6 of them didn’t have central confirmation, which is kind of interesting. We’re always going to see small differences. Our end point was the number of patients who are alive without progression at 6 months, and that was 50.4%.

We had to have a lower limit of the 95% confidence interval greater than 30%, and it was 41%. We definitely met the end point. If you looked at that tiny group of patients who had prior CDK4/6 inhibitors— in SOLAR-1, 44% of them were alive with disease progression at 6 months—it seems pretty good to me. Progression-free survival in this group of patients was 7.3 months, which is also pretty good.

Response rates were comparable, and most patients had a decrease in tumor size. Importantly, we looked at toxicity, and we saw similar issues as we had seen in SOLAR-1 with hyperglycemia and rash. We did again see that patients who took prophylactic antihistamines before they started or around the time they started the therapy had a marked decrease in severity rash and incidence of rash. Many fewer patients discontinued from because of hyperglycemia, clearly showing that people—when they get used to the treatment—are better able to manage the toxicity.

The dose intensity was higher actually in BYLieve than it had been in SOLAR-1. It wasn’t blinded, so everybody knew they were on it. The single-arm trials are important because we need to know how drugs that have gotten approved fare in the real-world situation, where everybody is getting CDK4/6 inhibitors.

We don’t want to randomize patients again to receive endocrine therapy alone. What we did was we used a real-world evidence cohort of patients who all had 

-mutated advanced breast cancer, and had all received prior CDK4/6 inhibitor therapy from the US Flatiron Health–Foundation Medicine clinico-genomic database to better understand how our data from BYLieve compared with the real-world setting. A few patients received capecitabine, and most received endocrine therapy with or without another targeted agent, like a CDK4/6 inhibitor on progression.

What we saw was that regardless of the way we weighted these different analyses and matched to them, we used a different way of matching. The progression-free survival appeared to be twice as long in almost all. Essentially, all cases were at least twice as long if not longer in the BYLieve cohort compared with the Flatiron cohort of patients, which included almost 100 patients. These are really encouraging data and really inform us in clinical practice about how we can use this PIK3CA inhibitor, alpha-specific inhibitor, and also that experience and education really help us manage the toxicity.

Significance of PIK3CA Mutation in HR+ Breast Cancer

 Unfortunately, resistance occurs over time. I know we're going to talk about your BYLieve data in a moment and targeting the PI3 kinase pathway, but broadly speaking, what are the major mechanisms of resistance that people are thinking about in terms of designing the next iteration of clinical trials to try to overcome resistance to CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors?

 This is such a great question, and there's been a huge amount of work on it. I think the advent of ctDNA [circulating tumor DNA] is helping us a lot, looking at cell-free DNA to try to have more accessible, real-time evolution of the genomic changes that predict resistance. I think it's important to keep in mind that we know there are also protein changes in mRNA [messenger RNA], not just the mutations in DNA. We really do not have great data on that, and that would require serial biopsies, which we really have a lot of trouble doing. Also, we believe that potentially one place you biopsy may not be totally reflective of the other place that you biopsy.

Our data are limited by this, but I think that as we're able to use big data and try to combine different mutations, we may be able to look at patterns of mutations and pathways that are affected, rather than single mutations. Albeit that we're limited right now by looking at single mutations rather than pathways, it's been fascinating to see that some patients have RB [retinoblastoma] loss that results in resistance. And it does seem like this group of patients who have loss of retinoblastoma may be severely resistant to CDK4/6 inhibitors, and maybe we should take another pathway in that particular group of patients.

A small group of patients have these mutations up front; they’re more likely to be acquired. We also know that patients who have 

 mutations, for example, benefit to a similar extent from CDK4/6 inhibitors but have a shorter duration overall of progression-free survival [PFS]. We've seen upregulation of cyclin E, or the CDK2 pathway, as well that seems to result in resistance over time. Then there are a number of other mutations that have come up. It's really interesting.

You get this genomic chaos over time, and as you see more mutations accumulate, it has been correlated with more resistance. We saw that in BOLERO-2, where in our subpopulation of patients who had multiple mutations, they faired very poorly. We weren't looking at serial mutations or much ctDNA because it was a new technology, but I think that trying to reverse these mechanisms of resistance has been difficult.

 can be mutated, and that's a resistance mechanism with very interesting data by Carlos Arteaga, MD, and a number of investigators have been looking at this. The drugs that target FGFR receptors are plagued by toxicity, and that's where there have been really nice preclinical data looking at the combination of CDK4/6 inhibitors and inhibitors of PIK3CA.

Again, those combinations have been plagued by toxicity. The only study that really showed that you could tolerably combine agents and see some benefit potentially was the TRINITI data, which were presented last year at ASCO [the American Society of Clinical Oncology annual meeting] by Aditya Bardia, MD, MPH. We participated in that trial. The majority of patients had received prior CDK4/6 inhibitors and had progression; they received ribociclib, a tiny dose of everolimus, 2.5 mg, and exemestane.

 mutations aside...and CDK4/6 inhibitors do not seem to care about 

 mutation so much, it's the hormone therapy, and they may overcome some degree of 

 mutation resistance. In these patients, 96 who had prior CDK4/6 inhibitors, the clinical benefit rate was 41%, and it was interesting that the progression-free survival was 5.7 months, much longer than we would have expected from giving a mini dose of everolimus and continuing a CDK4/6 inhibitor and giving exemestane. I thought that this was an intriguing triplet combination.

The problem is that the everolimus is off patent and people aren’t so excited because they want new agents. I think we're going to see a whole new class of drugs be included, the Akt inhibitors and these triplet combinations. There is also a lot of interest in just continuing a different CDK4/6 inhibitor after progression. You might want to be able to separate out the group of patients for example, who have RB loss, but it's such a tiny group, you could even do that retrospectively. There are a few ongoing trials looking at that, and there's been a lot of interest stimulated by a collection of data that, Joyce, you participated in where patients received a CDK4/6 inhibitor after progression. Those data were presented at ASCO last year, too.

 Aditya Bardia took the lead on that, and there were 5 institutions. We went through and did very in-depth reporting of the patient characteristics and the sequence of treatment. The bottom line was there were about 55 patients or so who had mainly had palbociclib, and upon progression whether they had benefited or not, at some point they had had abemaciclib subsequently, either immediately subsequent to palbociclib or at a later date. If you look at the overall population, again this is a case series, not a prospective trial, about 36% of patients had clinical benefit, so stable disease mainly, for 6 months or longer.

That's certainly been my practice experience. Interestingly, and I wouldn't have predicted this, the progression-free survival was longer with abemaciclib immediately following palbociclib, probably because it was an earlier line of therapy as opposed to getting it later after some subsequent chemotherapy, where there still was a group that benefited, but it was a shorter PFS. I guess that does make sense. I was always trying to separate them, similar mechanisms of action.

There is some degree of noncross-resistance there. Preclinically, abemaciclib has good activity against CDK2 and to some extent CDK1. There is some debate about whether the levels that are reached in humans will effectively block those other CDKs, and CDK9 as well. At any rate, it basically has a broader mechanism of action. It may be picking up some of these mechanisms of resistance that you were mentioning, Hope.

That's a case series, and there are other prospective trials going on looking at that a bit more formally.

Mechanisms of Resistance to CDK4/6 Inhibitors

 Tiffany, I have a similar question with the overall survival data: how do they impact differences between the CDKs [cyclin-dependent kinase inhibitors] that may lead you to think about different ones for different patients? I think there’s been a recent FDA meta-analysis of all of the data. Maybe you could update us on that?

 Yes, I’m happy to chat about that. I do share a lot of Hope’s approach in what she’s described in choice of endocrine partner as well as some of the differentiating factors around the CDK4/6 inhibitors. I think that from a benefit standpoint, we're seeing that the incorporation of CDK4/6 inhibition in a patient's treatment course, and certainly in the first-line setting, is advantageous.

The meta-analysis that you alluded to was a pooled analysis of CDK4/6 inhibitor data from the FDA that was published in early 2020. This looked at phase 3 studies of endocrine therapy and CDK4/6 inhibitors. They looked at 7 trials. There were more than 4000 patients in this analysis. They had almost 2 years of follow-up in that study, and across the board there was a significant advantage to CDK4/6 inhibition in terms of progression-free survival. The median absolute difference was almost 9 months, favoring adding a CDK4/6 inhibitor.

I think that we have all in multiple discussions been asked, is there a patient for whom you shouldn't use the CDK4/6 inhibitor? This pooled analysis showed that across all subsets that you could envision and imagine, the addition of a CDK4/6 inhibitor was preferred. They looked at line of therapy, they looked at partner endocrine therapy, AI [aromatase inhibitor] versus fulvestrant, and really across the board the advantage is there for the CDK4/6 inhibitor. That pooled analysis is looking at CDK4/6 inhibitors as a class and showing that it is better for your patient to have one than to not have one.

Oftentimes in practice I find choices based on toxicity. For abemaciclib I see a bit more in the way of gastrointestinal [GI] toxicity, so if somebody has some underlying inflammatory bowel, irritable bowel GI sensitivities, perhaps I would avoid that in preference of one of the others. We do know that abemaciclib tends to be a little bit easier in terms of myelosuppression, so sometimes for patients who have had difficulty with their blood cell counts previously, I'm more inclined perhaps to try abemaciclib for them.

We know that there are some monitoring differences between the 3 CDK4/6 inhibitors, perhaps attention needs to be paid to QTc goocorrected QT interval] prolongation, electrocardiography monitoring, and drug-to-drug interaction around ribociclib. Some of these logistical differences weigh in to patient preference and choice of CDK4/6 inhibitor, as well. I think that consistently, the data are showing us that the addition of a CDK4/6 inhibitor to endocrine therapy is of benefit for our patient.

 Yes, thank you. The data are getting stronger; we await the first-line data and the additional adjuvant data. Unfortunately, we did get the news during ASCO [the American Society of Clinical Oncology annual meeting] that the adjuvant palbociclib trial is not going to be able to meet its primary end point. We’ll have to wait to see the data to see what the considerations would be in that. However, we’re still waiting on palbociclib adjuvant data, the PENELOPE trial, in a very high-risk population with residual disease, and we’re waiting on the MONARCH 3 data in a high-risk population with abemaciclib. The NATALEE trial with ribociclib is still enrolling. We have a lot more to learn about patient populations who may benefit in the adjuvant setting.

 Although, you know Joyce, one thing about that survival data is so interesting to me because, other than the MONALEESA trial that combined first and second line in a higher-risk population, we haven't seen the survival data yet from the solely first-line trials. So more than 12 months from an AI, and this suggests to me that people live a long time, which is good.

If you take a bunch of patients that include 1000 with stage IIa disease and you say you need an end point by 3 years, maybe our expectations are all wrong. Maybe what we're really looking for is what's going to happen at 8 or 10 years.

 I agree totally. If you look at the history of our adjuvant trials, that's exactly right. People are doing too well, thank goodness; they're not recurring in 5 years. Most of the end points are 3 and 5 years. Absolutely, we'll wait and see, but that's the most likely scenario just based on our history, which of course is a good problem to have.

CDK4/6 Meta-Analysis Data

 In the first-line setting, the only trials that have shown survival so far is MONALEESA-7, as Denise said, in the premenopausal population with an AI [aromatase inhibitor] and a more aggressive disease, and then MONALEESA-3 with the fulvestrant; first and second line was a combined trial. The overall study was positive for survival, for the first and second line, there was a trend. They weren’t powered enough, but those are really important survival data.

There were survival data in the second line with both abemaciclib and with palbociclib; we're waiting the data. How do these survival data emerging impact what you do in the first-line setting? Given the MONALEESA-3, are you sometimes using fulvestrant in the first-line setting? What is your take on that?

 It's such a great question, Joyce. I think that there are many considerations. First we saw these really impressive survival data, and it occurs with subsets. I think we also learned from PALOMA-3 that if either your tumor needs chemotherapy or you get chemotherapy because that's what the physician does, we can't separate that, your PFS [progression-free survival] with next-line fulvestrant is shorter. Regardless of the use of a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor, you don't do as well.

I think that we all believe that hormone therapy, even in combination, is generally much better tolerated than chemotherapy, with a few exceptions of very toxic targeted agents. I think that it is really important, and Denise's data really make this point, that we should be using CDK4/6 inhibitors in combination with endocrine therapy rather than chemotherapy, except in very limited situations. So how do we decide on the endocrine partner in the first-line setting?

We had data from the previous trials that suggested that you might, if you had never had prior endocrine therapy in any setting, from FALCON, and you had soft tissue disease or bone disease, that you might have a better PFS with fulvestrant than with an AI. Anastrozol was used in that study. But of course the PFS data even in the best situation weren’t as long as we've seen in first-line settings with an AI and CDK4/6 inhibitor.

I always wonder, with this being such a unique group of patients, how do we decide which endocrine partner to use? We saw the data from the PARSIFAL trial at ASCO [the American Society of Clinical Oncology annual meeting] this year, which is helpful. It was trial done by the SOLTI network. They randomized patients to receive fulvestrant or letrozole with the CDK4/6 inhibitor palbociclib in the first-line setting. It's more of a real-life population, almost 500 patients. You had to have relapsed at 12 months or longer from the end of endocrine therapy or be endocrine naïve.

What was interesting was there was absolutely no difference in progression-free survival. Progression-free survival was quite nice. It was 32.8 months for letrozole and 28 months for fulvestrant. They were great data for our patients, at a median follow-up of 32 months. It didn't make a difference whether you had seen the aromatase inhibitor in the adjuvant setting either, which I think was incredibly encouraging for all of us to see. It also didn't make a difference whether you'd had visceral disease or nonvisceral disease.

There was some difference in numbers, but it was not statistically significant. All of these data together from PARSIFAL help me in that most of my patients would prefer to take an all oral regimen. I don't believe that you would only see a survival benefit with fulvestrant and you wouldn't see it with an AI in postmenopausal women, but you're going to see it in the patients with aggressive disease who are premenopausal. That just doesn't make sense from what we know.

So I would still favor the use of an AI with the CDK4/6 inhibitor if a patient has relapsed more than 12 months from an AI or has de novo metastatic disease. I would then use fulvestrant with the multitude of other partners that we are evaluating in the second- and greater-line setting. Maybe we'll be using oral SERDS [selective estrogen receptor degraders] in that setting in the future as well. I think that will make a big difference for us. In terms of toxicity and how we select CDK4/6 inhibitors, I try to rotate. I had done that with the AIs years ago and still do it.

We do sequence between them. I think that there are going to be fascinating data, and we'll talk about whether sequencing matters. I also think that we often try to use the trials themselves to decide how we use agents in a premenopausal patient. In the first-line metastatic setting, I tend to use ribociclib. In patients who have a lot of GI [gastrointestinal] problems, I might not jump to abemaciclib. But for people who have trouble coming in for blood counts, maybe abemaciclib is a better choice. Then palbociclib, of course we use a lot because it was the first agent to be approved.

CDK4/6 Clinical Trial Survival Data Impact

 Now let's move onto metastatic breast cancer, hormone receptor positive, HER2 negative. We'll turn to Denise because Denise had some interesting data from the MONALESSA-3 and 7 trials at ASCO [the American Society of Clinical Oncology annual meeting], which I'd like to hear her summarize. In the context of what's going on, are we getting some survival advantages with the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors?

 Thanks Joyce. It continues to be such an exciting time in hormone receptor-positive metastatic breast cancer again. It's been such a welcomed addition of the CDK 4/6 inhibitors in first-, second-, and later-line settings in the hormone receptor-positive patients. We were all excited when we had the initial look at the data from the PALOMA trial back in 2015, and then in 2017 we saw 3 CDK4/6 inhibitors get FDA approval.

I think we've learned how to embrace them in the practice. They have become a standard of care in the first-line setting for the hormone receptor-positive patients. I think when we look at the data from palbociclib, ribociclib, and abemaciclib, we continue to try to look at subgroups in the hormone receptor-positive patients, looking at patients with visceral disease, time of relapse, and what their prior adjuvant therapy consists of.

I think we see that exciting, resonating message of the efficacy of the CDK4/6 inhibitors. We have a challenge of trying to figure out who does not benefit from a CDK4/6 inhibitor in the hormone receptor-positive patients. We have our first-line trials. I think the MONALESSA-7 was an exciting trial, a bit unique in that it really tried to carve-out those premenopausal, perimenopausal patients who had participated in the other CDK4/6 study, but that was a dedicated trial. With that we see the issue in these premenopausal patients of a more aggressive biology. It was a different patient population in the sense of the key entry criteria for those patients.

That trial also looked at tamoxifen in combination with ribociclib, and due to an interaction, that arm was closed. So tamoxifen is not seen in combination with ribociclib. But the nonsteroidal aromatase inhibitors [AIs] have combined nicely with all 3 of the CDK4/6 inhibitors. What we've now tried to look at, and some of the data that I was able to present at ASCO, is that when we see this resounding message for ribociclib and abemaciclib of this overall survival and median progression-free survival advantage, we've looked at some of the hormone receptor positive-patients who present with visceral metastasis.

Are they different from our bone only or soft tissue presentations? I think traditionally that's been a presentation that I know many of my partners with a hormone receptor-positive patient who has had a metastasis in the liver or lung have shied away from an endocrine approach and really thought about chemotherapy for those showing disease in such a life-threatening organ.

The data that I was able to present are looking at both the MONALEESA-3, which was the 2:1 randomization of ribociclib with fulvestrant, and then the MONALEESA-7 with the premenopausal and perimenopausal group, looking at it in combination with an AI. The data looked at carving out those patients who presented with either visceral metastasis, specifically lung and liver, which was about 60% of those patients, and seeing how did they fare. Did they fare as well as patients in the overall population who gained a median progression-free and overall survival advantage?

I think the resounding message was the efficacy of the CDK4/6 inhibitors in combination with endocrine therapy in these presentations with perhaps considered more life-threatening disease in liver and lung, and showed a survival advantage and median progression-free survival advantage for those populations as well, at no increased toxicity. Sometimes we look at the liver in terms of being able to metabolize, or looking at the issues with a bump in the liver function test as a consequence of the CDK4/6 inhibitor.

None of that was exasperated in that patient population. I think there’s a lot of comfort now in not pulling a trigger for cytotoxic chemotherapy in the absence of a patient presenting with visceral crisis. Being able to look at a presentation with liver metastasis, lung metastasis, or both, and seeing that they too achieve a 20% and 30% reduction in the risk of death of starting out with an endocrine therapy in combination with ribociclib for their presentation of hormone receptor-positive metastatic breast cancer.

I know that gives us more confidence that, as we've seen with the overall population, when we really dissect into these subgroups of not just bone-only disease, but visceral metastases, we're seeing that same resounding message of efficacy in those subgroups. I think that gives us a lot of confidence of the role of the cell cycle inhibitors in combination with endocrine therapy as remaining the standard of care, no matter what those presentations are outside of the visceral crisis.

 Super, that’s so important, it's really paradigm changing. You've got survival data for the worst of these patients, unless like you said, they’re a total visceral crisis, which is uncommon. Otherwise, their survival is positively impacted by CDK4/6 inhibitors, through MONALEESA-7 and 3, ribociclib. We should be using much less chemotherapy in the first-line setting. On survival, it is emerging with these CDK4/6 inhibitor trials, and we have 2 endocrine agents, fulvestrant, an aromatase inhibitor in the first-line setting.

CDK4/6 Inhibition in HR+ Metastatic Breast Cancer 

 I want to just finish this segment by talking about how we sequence things for our patients. One thing I’d mention to pick up on what Hope said, is that in the approval for the sacituzumab govitecan, patients are required to have 2 prior cytotoxic therapies in the metastatic setting, unless they had recurred within a year of their adjuvant, neoadjuvant chemotherapy.

Within a year counts as 1 line of metastatic therapy, and then they only have to have 1 line of cytotoxic therapy. It's kind of second line in metastatic because those are pretty resistant type patients. Tiffany, how do you sequence things for the various subsets of our triple negative population?

 It is nice that we have so many agents to choose from now. I think as we've heard already in the discussions, when I hear triple negative breast cancer, I reflexively need to know what is this patient’s PD-L1 status for the tumor, and what is their germline 

 status? Increasingly, I'd like to have next-generation sequencing to understand some of their somatic chartable mutations.

For those patients who test PD-L1 positive, if they're more than 6 months from their adjuvant therapy, I would be considering using a first-line checkpoint inhibitor in combination with chemotherapy. For those who also may be germline 

 positive, this is trickier, as Denise already alluded to, but we do have that overall survival data from IMpassion, and I think that's quite compelling. I probably would err on the side of incorporating that checkpoint inhibitor in the first-line setting and then considering PARP inhibition for those patients next.

Soon, my hope is that we won't have to choose either/or, but there are studies going on right now looking at combinations of PARP inhibitors and checkpoint inhibitors. Maybe for those patients who are fortunate enough to have 2 biomarkers, we'll have a little bit better direction. For those patients who are PD-L1 negative and lack a germline mutation, I still will strongly consider clinical trials in the first-line setting. We have a lot of work to still be done here.

 mutations or PI3 kinase mutations, TNBC [triple negative breast cancer] may allow for some targeted therapies in the first-line setting. Some trials going on right now are the IPATunity and trials with capivasertib and other AKT inhibitors. Sacituzumab is a great new agent, and having participated in ASCENT and some of the earlier phase 2 studies, it has great activity. We all struggle with those patients who potentially have seen 5 drugs in the early stage setting for their really high-risk TNBC, and unfortunately, recur rather quickly.

I think in this space, if they lack PD-L1, I see the moving up sacituzumab to perhaps the second line as you alluded to already. Eribulin is also very much a standard-of-care chemotherapy with activity in TNBC that I in practice tend to move up earlier if a trial isn't available for my patient.

 OK, thank you. How about you, Denise, how do you sequence things?

 Like Tiffany, I think in the first-line setting we were really looking at testing for the PD-L1 presence to give that opportunity of atezolizumab in combination with nab-paclitaxel to give those patients that overall survival advantage that we've seen. In addition, we look for the germline 

 mutation, and I go for the overall survival and would sequence with a PARP afterward. I think we increasingly do these metastatic tumor biopsies to do the next-generation sequencing to identify any other actionable targets, largely to get patients on clinical trials.

That is where the targets are outside of the PD-L1. Outside of that, I think I'm back to looking at sequential chemotherapy agents and selecting them based on what the patient was on. I'm a big fan of eribulin in this setting. Most of the patients have seen an anthracycline and taxane, so we look at that if they haven't utilized a platinum like the gem-carbo [gemcitabine/carboplatin] combination in these patients.

I think continuing sometimes to use time with chemotherapy and then look back at what opportunities are coming forth with the clinical trials and trying to sequence them. Some patients require 2 priors, so I get my standard-of-care chemotherapies, and then get them on these clinical trials. Some are first-line PD-L1 negatives, and that's where I channel those patient populations. I think always trying to look at what we have standard of care and what we have with the ability to integrate a clinical trial at any point in the course of that patient's disease.

 Super. Why don't you have the last word here Hope about other combinations, but also anything you want to add with regard to sequencing.

 I agree with the sequencing issues. I'm really intrigued to see whether the addition of agents that target the PIK3CA pathway may make a difference and with immunotherapy enhancing the immune response. I think that's a really interesting area, but we've seen a lot of very intriguing single-arm data that don't pan out in the randomized trial setting, so I don't think we should be doing this outside of trials.

I think one of the interesting things about these agents, these antibody drug conjugates, as a class is that may be beneficial across different disease groups regardless of the antibody. For sacituzumab govitecan, I had mentioned this basket trial where they looked at different diseases and different subsets, and they also looked at hormone receptor-positive breast cancer in the metastatic setting heavily pretreated, and patients showed an impressive response rate that was quite durable.

The ongoing TROPICS trial is the phase 3 trial design, very similar to ASCENT, that's looking at sacituzumab govitecan versus chemotherapy of physician choice. It briefly held enrollment due to the COVID-19 [coronavirus disease 2019] pandemic and has opened up again. I'm hopeful that we could rapidly accrue to this trial and allow additional treatment options for our patients with metastatic hormone receptor-positive disease that represents such a big group that we treat.

Interestingly, trastuzumab deruxtecan is also being tested in this HER2 low population, of which a subset have triple negative disease. We may see some data from this; it's odd to use trastuzumab, but maybe it's through this hypothesized bystander effect, which it must be drug leaking out all around. It also has a really high drug-to-antibody ratio, so that's going to be interesting to see as well because that's a randomized phase 3 trial that's ongoing.

In terms of other sequencing, how we use checkpoint inhibitors, I mentioned that it's relatively tragic only 40% of patients can benefit from checkpoint inhibitors from what we know now in the metastatic setting. We will always see de novo metastatic disease, and we know these rapidly progressing tumors don't benefit very much either. One of the ideas is to try to enhance the effect.

Tiffany mentioned this, there is a trial going on called KEYLYNK-009, which has an induction with pembrolizumab, gemcitabine, carboplatin, and then randomizes patients after induction to either receive a PARP inhibitor and pembrolizumab versus continued chemotherapy and pembrolizumab. I think that's going to be fascinating as well based on the data that PARP inhibitors may enhance the host immune reaction to tumor through the STING pathway and interferon. That will be very interesting.

 Yes, super interesting, there's lot going on—AKT inhibition ipatasertib, capivasertib, immune-oncology, PARP inhibitor combinations, etc. I’ll finish by saying that with sacituzumab, I find that it's pretty much of a go-to agent now, and I think the more drug resistant the patient has shown herself to be, unfortunately, the earlier we're going to be trying to use it. I'm basically using it as soon as I can in the metastatic setting. Because irinotecan has a long history of being noncross-resistant with the agents we have available, we just don't go after that target. It's a new target; it can be quite helpful to patients with some very durable responses, as everybody has said.

Next-Generation Sequencing: Triple Negative Breast Cancer

 We have got 1 more therapeutic option that is pretty new to our practice. I thought we might talk about sacituzumab: what we know from the available phase 2 data, what was said about ASCENT, the phase 3 trial, and a refresh for our memory about the data.

Then we want to finish up the discussion by how we incorporate sacituzumab; we've talked about checkpoint inhibitors, PARP inhibitors, now we'll talk about sacituzumab govitecan. How do we do the first line, second line, third line for our various emerging subtypes of triple negative? Hope, could you summarize for us what you’re thinking about sacituzumab?

 I'm happy to. I think it's been very exciting for us to have another agent approved in the treatment of patients with resistant triple negative breast cancer [TNBC]. Of course, we're very interested to see how this antibody drug conjugate [ADC] fares in earlier-line therapies in different combinations, even in the neoadjuvant setting. Sacituzumab is in the ever-popular group of drugs now called antibody drug conjugates, and it's a fascinating antibody against Trop-2, which appears to be highly expressed in most subsets of breast cancer, if not all. It's linked to a novel toxin, and it's the metabolite of irinotecan SN-38. It has a high drug-to-antibody ratio similar to the current new class of antibody drug conjugates, where it's really double what we saw for T-DM1 [trastuzumab emtansine].

That may have an impact both on efficacy and toxicity, of course, but also on some bystander effect type of response that we may be seeing. Sacituzumab is dosed differently than some of the other ADCs; it's given day 1 and day 8 every 3 weeks, and it was initially tested in a phase 1b expansion, where there were a number of different tumors that were tested in different subtypes. In that initial expansion, there were exciting response rates seen in patients who had received 3 to 5 prior lines of chemotherapy.

That is hard because patients with very resistant triple negative disease don't get to 5 lines of therapy, unfortunately, due to poor responses and organ dysfunction. In these patients who were heavily pretreated, there did seem to be good and durable responses. This trial was expanded to include 108 patients, which was the number that was used for the FDA accelerated approval. This is a single-arm trial, and it's similar to what we just saw for trastuzumab deruxtecan; you can have a single-arm phase 2 study that meets an unmet need, like heavily pretreated patients who received most prior treatment.

If you have good efficacy data and reasonable toxicity, you get accelerated approval, but you have to show that it's better than a standard in a randomized phase 3 trial to get final approval. The overall response rate in those 108 patients who were heavily pretreated was 33%, and almost all were partial responses, but about 3% had complete responses. The median response duration was almost 8 months, going out to 11 months, which is certainly better than we see with anything else that we treat patients with in the third-line or greater setting.

The range actually went out for some patients who are on drug for more than 2 years, and we don't really know who those are, which was really amazing. There were about 17% of patients who stayed on treatment for more than 12 months, which was amazing. The drug itself is reasonably well tolerated. It's interesting, going into these studies we thought the biggest issue would be diarrhea, based on irinotecan. Diarrhea occurs, but it's pretty easily managed with education and using antidiarrheal medications as needed.

 polymorphisms that had been looked at in irinotecan because it really hasn't been associated with more diarrhea at the moment. I think it just has to do with the amount of exposure to free drug. You must educate patients, but it's usually pretty well managed. Neutropenia, however, is very common. About 65% of patients had at least some grade of neutropenia, and 43% had grade 3 to 4 neutropenia. Thrombocytopenia was rare; anemia is the usual problem we run into.

For the neutropenia, I think that what they did in the trials and in the ASCENT trial, is require an ANC [absolute neutrophil count] of 1.5 going into each new day 1 of a cycle. In clinical practice, we’re much less likely to use that. We use an ANC of 1. I think that we have to have a low threshold for using growth factors in patients, and in fact, my approach has been since the approval is that if a patient needed growth factors for gem/carbo [gemcitabine/carboplatin], or eribulin, they’re going to need growth factors for sacituzumab, so you might as well start out using something; you can always back off.

It works pretty well. Some people have even used pegfilgrastim after the day 8 because you have 2 weeks, although that certainly is by investigator decision. Then the final trial that will lead to approval is ASCENT. The ASCENT trial had a press release just before the approval that demonstrated that they reached their primary end point with a progression-free survival benefit comparing sacituzumab govitecan to chemotherapy of physician choice in the third line or greater. These are very exciting data. We look forward to seeing it sometime later this year, but it hasn't yet been presented. There just aren’t data yet.

The other thing to briefly mention is that alopecia is seen with many of these new antibody drug conjugates; 38% of patients had grade 1 or 2 alopecia. You do have to warn patients that they can lose their hair, and we don't yet know if scalp cooling works. Alopecia is also seen with the other ADC that recently had accelerated approval, trastuzumab deruxtecan. A lot of people can keep most of their hair, but you have to warn patients because it's a big issue in the metastatic setting.

Phase 3 ASCENT Regimen Accelerated Approval

 The SWOG S1416 is really the first data in triple-negative breast cancer that has shown benefit from the addition of a poly [ADP-ribose] polymerase [PARP] inhibitor, which makes it really exciting. I think the genius of that trial was the definition of the breast cancer gene-[

] like population. It needs a prospective follow-up trial of course, but it is a very nice attempt to define this group that may have homologous recombination deficiency beyond the germline 

The group is not ready for prime time. We do not have veliparib available, but it is a very nice hypothesis generating trial. The lack of benefit from veliparib in the germline 

 patients stands in contradistinction to the BROCADE 3 where patients received paclitaxel carboplatin with or without veliparib, and the curves were on top of each other for the first 6 to 8, 9 months, and then they split because the patients had the opportunity to stop the chemotherapy and continue veliparib versus placebo as maintenance therapy at their physician's discretion. There was this nice tail on the curve with the veliparib with maintenance strategy, and in the SWOG 1416, there really was not much.

They are waiting still for the data to be fully analyzed, but they really don't think there was very much in the way of a maintenance strategy. We will have to wait and see those data, but that is probably going to explain the difference there. It looks like we may be able to eventually go to a maintenance strategy for veliparib, hopefully based on the Brocades 3 data.

Those are really hypothesis generating for the future, but for our practice, I really want to see what Denise thinks about the TBCRC 048. Is this ready for our practice on Monday morning? The 2 findings were pretty clear from that trial, I thought. What do you think?

 I agree. I think you know we have been struggling a bit about how to incorporate the PARP inhibitors into practice and for which patients. I think it's an easy thought to think about just our 

 patients, but now that we have so much profiling and we're looking at now what do we do when we have a somatic 

 mutation? I think as we step back, this is a great segue into trying to figure out, the approaches to triple negative breast cancer. I think it brings in the role of genetic testing to identify the 

for the patients that never received genetic testing in the adjuvant setting.

It is certainly a dialogue I picked up with patients and say, “We have a therapeutic agent that may benefit.” Some patients had been approached in an adjuvant setting and may not have felt strongly about it, but I think I use that as a way of reintroducing it because there is a therapy tied to it. I think likewise for profiling patients, it is another trigger of maybe we don't always find a target that's actionable.

When we see this data, you think there is a reason to profile these tumors and try to identify them even though they're not a germline but are somatic mutations. I think we are going to continue to evolve with some of the other mutations like the ataxia-Telangiectasia mutated and checkpoint kinase

 to be able to continue to increase the armamentarium for these triple negative breast cancer patients and be able to use these targeted agents as single agents here with the PARP, to look at it, and then again utilizing in our triple-negatives testing for the PD-L1 with SP142 that we've touched on, to embrace that population that's going to be eligible for the consideration of immunotherapy.

I think now the hard part may be in how do we sequence someone that has a somatic or germline mutation and may be PD-L1 positive? It kind of opens a Pandora's box in a nice way. I think looking at survival data is important, so that may be a segue of looking at how to use or sequence if you have a PD-L positive and a 

positive somatic or germline patient. I think it just broadens the horizons of how we think of triple negative, and we have kind of learned that in itself is a very heterogeneity population.

It merits an investigation and to tease out the subpopulations in triple-negative breast cancer because I think we have exciting targets in agents to improve the outcomes from these patients and to continue offering therapeutic choices that could keep these patients and quality of life and with stable disease.

Thank you. The time for next generation sequencing is here, and reintroducing it to the clinic, reintroducing the idea of germline testing now even more with the 

 data. How about you Hope. Are you thinking about the germline PALB2s as a somatic 

? Would you consider using olaparib for those patients?

I already have. We participated in that trial, and I enrolled our only patient at our institution, who had 

 mutation and did have a prothrombin ratio, but then it rapidly progressed in brain. I'm really interested in trying to get these drugs earlier in the course of therapy, and a lot of these patients with mutated 

 have hormone or are hormone receptor positive. I think the OlympiAD trial would be really helpful for us in the adjuvant setting to try and better understand if we can take patients with high-risk disease and change their outcome by giving these agents earlier.

 mutations. I think, to Denise's point, looking at the somatic BRCA-mutant patients and other mutations that cause DNA repair defects is going to be interesting. This trial underneath Nadine Tung's leadership through our consortium will expand and include additional patients and expand to various groups, so that we'll have even more data.

I think it's really important and having these agents is important as well. I think for the SWOG is interesting to me because the hazard ratio for this 

-like group was 0.53, but the difference actually in progression-free survival was very small. It was just about 1.7 months, and they did suggest this survival difference although it wasn't statistically significant; I think their numbers are really small.

I wonder how many of these patients might have had somatic mutations in

 versus those who had the HRD [homologous recombination deficiency] defect alone without somatic mutations. You know it's going to be interesting over time to see that. I also wonder if some of the differences seen here versus the Brocades trial have to do with the poor tolerance of cisplatin. Having seen patients who enrolled on that trial who were miserable on the cisplatin, you wonder whether or not the choice of the DNA damaging chemotherapy is important here as well.

SWOG S1416 and TBCRC 048 Phase 2 Trial Overviews

 Another really important topic in the very rapidly evolving landscape in triple-negative breast cancer germline breast cancer gene [BRCA] patients is the topic of poly [ADP-ribose] polymerase [PARP] inhibitors. There were interesting data sets at American Society of Clinical Oncology [ASCO]. Some may be perhaps immediately practice-changing, and then another one that I think is real forward looking. Tiffany, why don't you give us a summary of where we are with PARP inhibitors and your take on some of the new data.

I'm happy to. I think we've all had some time to digest the data from OlympiAD and from EMBRACA that led to the FDA approvals of both olaparib and talazoparib for patients who carry germline 

 mutations. Just as a reminder, the OlympiAD study was a randomized trial of olaparib versus treatment of physician's choice. This was for patients with known pathogenic germline

In that study where the primary end point was progression-free survival, the single agent PARP inhibitor actually was associated with about a 3-month improvement in median progression free survival [PFS] over the cytotoxic chemotherapy. Actually, a lot of the quality of life and toxicity measures really favored the PARP inhibitor over cytotoxic chemotherapy. An interesting follow up in the OlympiAD data was a subset analysis of those patients treated in the first-line setting, and olaparib was associated with about a 50% improvement in median overall survival over chemotherapy of physician's choice.

If we look at the EMBRACA data that led to the talazoparib approval, EMBRACA was also a randomized phase 3 study of a single agent PARP inhibitor up against treatment of physician's choice. Very reasonable control arm chemotherapies such as capecitabine, gemcitabine, vinorelbine, and, similarly, talazoparib was associated with a significant improvement in median PFS: about a 3-month absolute difference there, and about a 40% to 50 % improvement in PFS.

We have some interesting new data; Jennifer Litton presented at American College of Radiology about the overall survival data from the EMBRACA study and there after a follow up of almost 4 years. There really was no apparent significant difference in overall survival in the overall study population for talazoparib versus standard-of-care chemotherapy, and median overall survival was about a year and a half or about 19 months. There are no overall survival data that was proven with the talazoparib agent, and we do have some data in a subset analysis for overall survival benefit from olaparib.

That's where we've been until ASCO where we had 2 really interesting presentations, both looking at the potential advantage of PARP inhibitors beyond just germline 

 mutations. I think that the first study that I'd like to spend some time looking at was the SWOG trial that was presented; this was a SWOG S1416. This was a randomized phase 2 trial in patients with triple negative breast cancer or known germline 

 mutations, treated in the first or second line. Patients were randomized to either cisplatin monotherapy or cisplatin in combination with veliparib.

I'm making a note because we do have some other trials that have previously reported on veliparib. In this particular trial veliparib was dosed at 300 mg twice a day for a 14-day continuous regimen. This is a much higher dose than what we have seen in previous studies such as BrighTNess and BROCADE. In this trial of cisplatin versus cisplatin plus veliparib, the primary end point was PFS but in some unique subsets or specified subsets. One subset of interest was those patients with germline 

A second subset of interest was those patients who had 

-like triple-negative breast cancer. That was defined in a number of different ways. You could have a homologous recombination deficiency [HRD] assay with a cut point of greater than 42 suggesting you have a BRCA-like cancer. You could have a somatic 

 mutation in the tumor to be classified in this way. You could have 

 promoter methylation, and you can have germline mutations in other genes besides 

 that are known to have HRD deficiency regulation. That class of tumors were considered 

Then the last subset to be looked at were those that were non­–

-like tumors. These patients in the study had no prior exposure to cisplatin or PARP inhibitors. More than 300 patients were randomized in the phase 2 study. The majority of them were really first-line patients, almost three-quarters of the patients were treated first line as opposed to second line, and when you look at the characteristics of these patients only about 13% carried a germline 

About half of the patients were classified as 

-like. I think that the really big, exciting take-home message from all of these analyses of the SWOG study was that in the patients that were reclassified as 

-like triple-negative breast cancer, there was about a 50% improvement in PFS in those patients. The PFS increased from about 4.2 months to almost 6 months, and that was also associated with an improvement in response rate from about 30% to 45%.

This met statistical significance. They looked at overall survival for this 

Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center

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