A four-part VJSession with leading experts Erika Hamilton, Giuseppe Curigliano, Sara Tolaney and Andrew Tutt, who offer their perspectives on the exciting developments in the field of breast cancer presented at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting.

Welcome to The Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).

This exclusive roundtable discussion features leading breast cancer experts Erika Hamilton (Sarah Cannon Research Institute, Nashville, TN), Giuseppe Curigliano (University of Milan, Milan, Italy), Sara Tolaney (Dana-Farber Cancer Institute, Boston, MA) and Andrew Tutt (The Institute of Cancer Research, London, UK).

Watch this on-demand feature to learn about the exciting breast cancer advances from ASCO 2021 and gain exclusive insight into the OlympiA trial and PARP inhibitors, the ECOG, GeparNuevo and BEGONIA studies, the use of CDK4/6 & BCL-2 inhibitors, SERDs, and much more.

OlympiA & olaparib

“It really highlights the critical importance of testing our patients for genetic mutations. So, it’s going to be really important that we know which patients have germline BRCA mutations.”

     – Sara Tolaney

“I think one of the big changes is how we think about patients with hormone receptor-positive forms of breast cancer, who we may not have been as triggered to refer for genetic testing. I think this really does make us need to think really much more about that and in that population of patients, because it could well change the treatment paradigm for them”

     – Andrew Tutt

Capecitabine, GeparNuevo & BEGONIA

“I was impressed by the results of combining, of course, durvalumab with trastuzumab deruxtecan. Very few patients, so let’s advise the people that here we are discussing a very few patients, but [they] provide the rationale to combine, maybe in the neoadjuvant setting, a HER2-positive disease and maybe in some HER2-low immune checkpoint inhibitors with antibody-drug conjugates. I really believe this combination should be explored at  first also in the metastatic setting, because we cannot ignore the risk of toxicity…But the potential to combine the both of them is impressive because you can induce immunogenic cell death with the trastuzumab deruxtecan, and then you boost the immune system with the durvalumab.”

     – Giuseppe Curigliano

CDK4/6 inhibitors, SERDs & BCL-2

“I know there are many first-line trials comparing SERD, CDK to AI CDK. While I think it’s an important thing for us to study, I’m also a little cautious about it, because we saw data from PARSIFAL that had suggested in endocrine-sensitive patients, maybe your choice of endocrine therapy doesn’t matter with the CDK 4/6 inhibitor. And so, I think we need to learn more. I think we’re hoping they may prevent emergence of ESR1 mutations and maybe they’re going to help extend PFS, but I think we need to know. I know there’s a lot of interest in also moving these agents into the adjuvant space and how we do that best, I think we’ll need to see, but I’m very hopeful about them, but again, awaiting the randomized data.

     – Sara Tolaney

Talazoparib & looking forward

“I believe in the future, we need to better identify those patients who can do a deescalation in the metastatic setting, also in the adjuvant setting. If you look at the data of ADAPT-ER in which a short exposure to endocrine therapy can modify also the biology of a cancer that may have a better prognosis. So, Decrescendo will be the future.”

     – Giuseppe Curigliano

“ I think we’re really moving towards personalization. So whether it’s using germline testing to select patients for therapeutics or genomic alterations, or even I’d see markers now for ADC selection, potentially, I think this is our movement forward, is how can we best personalize care to improve outcomes and decrease toxicity. ”

     – Sara Tolaney

Full Transcript
Erika Hamilton:

Thank you for joining us on behalf of VJOncology. We're excited to recap some of the most exciting data from ASCO 2021 in the breast arena. I'm joined with three other panelists here. I'm Erika Hamilton. I lead the breast cancer research program at Sarah Cannon Research Institute in Nashville, Tennessee. I'm also joined by Sara Tolaney.

Sara Tolaney:

Hi, I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber in Boston. Great to be here.

Erika Hamilton:

Thank you. And also joined by Andrew Tutt.

Andrew Tutt:

Hello, I'm Andrew Tutt. I'm the director of Breast Cancer Now Research Center at The Institute of Cancer Research and Guy's Hospital King's College London.

Erika Hamilton:

So first off, I think, Dr. Tutt, you stole the show at ASCO this year with your presentation of OlympiA. Would you be kind enough to walk us through that data a little bit and where you see it fits in with practice currently?

Andrew Tutt:

Thank you very much. It was a great privilege to present OlympiA on behalf of the partners. So OlympiA is an ongoing study, but it is a phase three randomized trial conducted by the partnership of the Breast International Groups and NCI CTEP groups with support from AstraZeneca and Merck testing the role of the PARP inhibitor, olaparib, after standards of care local, regional, and adjuvant systemic treatment in patients with germline mutations in the BRCA1 and BRCA2 genes and HER2-negative breast cancer with a high risk features for distant recurrence sufficient to have needed to have at least six cycles or standard of care chemotherapy, either in the neoadjuvant or adjuvant setting. The main results of the study which tested a year of treatment with olaparib against the placebo were a highly statistically significant effect on the primary endpoint of invasive disease-free survival with a hazard ratio of 0.58 at a p-value of less than 0.001, an absolute difference in three-year disease-free survival of 8.8%.

Andrew Tutt:

I think it was important to note that this was a primary analysis performed early, because it was stimulated by crossing a superiority boundary at the interim analysis point and recommended for reporting by the IDMC. So, we were very keen to look in a pre-specified analysis of a mature population within the study. The first half of those patients accrued, first 900 patients out of 1,800. We saw the same hazard ratio for the IDFS effect in that population. So, the IDMC and we, at primary analysis, were confident that this was a sustainable result. We could go on and test the very important secondary endpoint of distant disease-free survival, which again was a hazard ratio of 0.57, highly statistically significant with an absolute difference of 7.1% at the three-year IDFS rate.

Andrew Tutt:

Overall survival, very early really with a median follow up of only 2.5 years in the ITT population. so, alpha was conserved for future analysis. Although the hazard ratio is 0.68, the p-value is 0.024, and that is actually not statistically significant in the statistical analysis plan because we're saving alpha for the data. So the headline really was that the primary endpoint was met. The safety data showed adverse events very familiar for the drug and its current indications and with no strong negative safety signal and reassuring preservation of quality of life, global quality of life measures between the placebo and the treatment arm.

Erika Hamilton:

Great. Thank you so much for that. I guess a question that a lot of people are going to have is do you anticipate an approval based off of this? Because olaparib is already approved, do you anticipate maybe providers being able to get this for their patients ahead of the formal approval?

Andrew Tutt:

I mean, it's clear that there will be a conversation between AstraZeneca, Merck and global health authorities in the fullness of time to seek approval, or the timing of which I think we don't know as academic investigators, but we certainly anticipate those conversations happening. At the moment, it is not an approved medicine in this population of patients. I really don't feel comfortable commenting on whether people should go beyond the licensed indication to prescribe this medicine. I think this needs to be looked at by the global health medicine regulators. We hope those conversations can proceed now with a very good data set that has been published and which is in the hands of those pharmaceutical companies.

Erika Hamilton:

Great. Thanks. Sara, so I can see a lot of downstream effects of this study. What do you think are some of the other things that this study may ultimately change for us?

Sara Tolaney:

Well, first, I will say these are amazing results to see. A 40% reduction in IDFS events I think is really practice-changing. And so, I think I already say, I have patients who have called who have germline BRCA mutations who are asking, "Should I be getting olaparib now?" And so, I think this is a question that is going to... This is really going to change our prescribing practices. But I think moreover, it really highlights the critical importance of testing our patients for genetic mutations. So, it's going to be really important that we know which patients have germline BRCA mutations.

Sara Tolaney:

I think Dr. Tung did a great job in her discussion at ASCO, really highlighting this problem that in fact, we are undertesting patients in the early disease setting and I'm hoping this will change things. I think it changed our practice in the metastatic setting when we got data from OlympiA, then in BRCA, where I think we didn't start to become better at offering genetic testing to a metastatic patients knowing it had therapeutic implications, but now it does in the adjuvant setting. And so, I think we really need to bring this to light and make sure we are offering genetic testing to all our patients.

Erika Hamilton:

Yeah.

Andrew Tutt:

Would it be okay for me to comment on that as well? Again, I agree with Sara that Nadine Tung did a very nice discussion at this. I think although it's quite common in global practice now to test patients with triple-negative breast cancer, sometimes regardless of family history, I think one of the big changes is how we think about patients with hormone receptor-positive forms of breast cancer, who we may not have been as triggered to refer for genetic testing. I think this really does make us need to think really much more about that and in that population of patients, because it could well change the treatment paradigm for them. I think we're also much more... I think these data mean that this is not just something that you think about in the risk clinic. This is something that you think about in your treatment clinic.

Andrew Tutt:

You can get results back now in a timeframe that you can use to have a conversation with patients about what their treatment strategy might be. In the past, it might take six months and be terribly, terribly expensive to do. We're associated with very complex counseling. I think this is making us think. This is one of the bits of data that I think will make us think that maybe we should be more comfortable as oncologists to suggest testing, to know that we'll get the result back quickly and it will be performed or can be performed cheaply. And that if that result is positive, there may be further things to counsel about with regard wider family history, but that can be engaged if needed. We could consent the person to attest rather than them have to go through a deep counseling process beforehand. We need to think that through, because it will make it much more practical to do the testing in the oncology clinic and get a quick result.

Erika Hamilton:

Yeah, I completely agree with both of you. It really wasn't until the approval of olaparib and talazoparib in the metastatic setting that our access to uniformly test HER2-negative patients in the metastatic setting came about. So, I agree. I think that we're going to see some changes in guidelines about broad testing and until we test based on this. So, Giuseppe Curigliano has joined us. Giuseppe, would you introduce yourself?

Giuseppe Curigliano:

Hi, good evening. My name is Giuseppe Curigliano. I work at the European Institute of Oncology, Milano. Thanks for inviting me.

Erika Hamilton:

Absolutely. So, we've just finished discussing OlympiA and what we really think are going to be practice-changing results here. Sara, I may ask you to comment on the ECOG study specifically about adjuvant capecitabine versus platinum and what your takeaway is from that abstract were?

Sara Tolaney:

This was a really interesting study that Ingrid Mayer presented at ASCO, really trying to assess in a patient who has residual disease after neoadjuvant therapy that is triple-negative and specifically is also basal-like subtype, looking to see if platinum chemotherapy would be better than capecitabine in this group of patients. I think we've had a lot of questions about what the role is of platinum in early disease, and also how widely applicable the CREATE-X data are from capecitabine and if we could do better. And so, this study took those patients who had residual triple-negative disease. But in fact, the eligibility was different than CREATE-X because you actually had to have residual T1c disease. You had to a bit of disease that was left.

Sara Tolaney:

And then it's specifically looked at IDFS in the basal-like population, really comparing four cycles of platinum therapy, either cisplatin or carboplatin propositions choice to six cycles of capecitabine. In fact, what we saw was that in essence, there was no real difference in the IDFS. But to me, the bigger thing was that the IDFS was actually quite poor in both arms. So at three years, the IDFS was 49% in the capecitabine arm and 42% in the platinum arm. This is not what I was anticipating. I think it's worse than I would have anticipated. But again, I think these are patients who did have T1c residual disease and basal-like disease. I think what we're seeing is that certainly platinum is not superior, but it's also non-inferior. So I think it leaves us with capecitabine as the current standard in someone with residual triple-negative breast cancer, but it also means we need to do better.

Erika Hamilton:

Yeah, absolutely. I think that brings up a good point. So, in OlympiA, specifically, patients receiving adjuvant capecitabine were excluded, so the so-called CREATE-X regimen. Giuseppe, how do you integrate these? If we end up with olaparib approval, we obviously have the option of giving patients capecitabine as well. Do you see the PARP inhibitor data really trumping the CREATE-X data here for those patients that may have BRCA alterations?

Giuseppe Curigliano:

Absolutely, yes. I believe the data Andrew presented should change practice since next week. Because in my opinion, here, we have a special population of patients that are BRCA mutant, germline mutant. Any patient with this type of mutation that we consider at high risk should receive a PARP inhibitor in the post-neoadjuvant setting or in the adjuvant setting, if you consider the high risk. I don't believe that we will never do a trial comparing olaparib with capecitabine in this patient population. Personally, I believe that olaparib would be superior to capecitabine. I believe the only question is related maybe to the patients ER-positive, even if in my opinion, rather than giving CDK 4/6 inhibitors in this patient population, since they are germline BRCA mutant, they should also receive olaparib. Even if they are HR-positive, I will not consider a CDK 4/6 inhibitor in this patient population.

Erika Hamilton:

Yeah, I think that's really helpful for practice. I guess the other hot topic in early breast cancer right now is immunotherapy in the triple-negative space. Dr. Loibl presented a data from GeparNuevo, really looking at the addition of durvalumab to chemotherapy. This adds to our body of evidence and previously reported studies with the tislelizumab and pembrolizumab, et cetera. But what's your takeaway from that abstract? Maybe, Giuseppe, I'll go back to you. Where do you think we may end up incorporating this? Do you think it's ready for prime time now or not?

Giuseppe Curigliano:

No, absolutely. My opinion, it's not ready for prime time. The data of the GeparNuevo, of course, are of interest. I believe that the benefit to that has been observed in the durvalumab arm should be better analyzed and should be, of course, considered for future trial, but the study was underpowered to demonstrate a benefit in terms of overall survival. So even if the data are of great interest, I really believe those are not practice-changing. In the data, finally, we have a benefit in terms of a distant disease-free survival. When comparing to the placebo arm, it was 91.7% versus 78%. Also, there is a trend in terms of overall survival benefit, 95.2 versus 83.5, but the trial was not designed to have as a primary endpoint overall survival. The primary endpoint of GeparNuevo was a pathological complete response. So even if data are really interesting, even if I was enthusiastic about this, because I hope that in the other trials, we will have the same results, the data of GeparNuevo are not practice-changing.

Erika Hamilton:

Yeah, absolutely. Does anybody else have anything to add to this?

Andrew Tutt:

Erika, may I just come back briefly to the capecitabine discussion if that's okay [crosstalk].

Erika Hamilton:

Absolutely.

Andrew Tutt:

It's just because I know that there've been some questions about this, why we didn't have capecitabine to be in as a control in OlympiA. This is an issue of timing. So OlympiA started in 2014 and ended in 2019. CREATE-X is published at the end of 2017 and didn't really influence practice outside Japan and Korea, Taiwan until 2018 plus really, and in many countries still doesn't completely. It wasn't that we deliberately didn't include it. It was not the standard of care. I think I would just point people to the fact that this OlympiA is in basal-like breast cancer with the triple-negative group, at least, basal-like breast cancer with a BRCA mutation of biologically refined group of patients in which we have no real understanding of what capecitabine performance is, except that the ECOG-ACRIN study certainly says there's a heck of a lot that we need to do better in for basal-like breast cancer, where I just think they look equally appalling as therapeutic strategies, carboplatin and capecitabine.

Andrew Tutt:

So I think I would regard the BRCA carrier population, I would have it driven by the result of the OlympiA rather than capecitabine. People have wondered, should they wait, and maybe when the medicines approved, obviously wait, give six months of capecitabine and then give olaparib. All I'd say there was have a look at those survival curves and look how many events are going to happen in those six months that you're giving capecitabine. Do you really think you're going to prevent those events happening in a BRCA carrier with basal-like breast cancer with capecitabine when you know that you might prevent them with olaparib based on the data? Bad things happen early, and I'm not sure that that six months of therapy with capecitabine is that helpful.

Erika Hamilton:

Yeah, I agree with you there, right? This is a targeted option with a predictor of response, so it's a hard sell to not offer a patient that immediately, right?

Andrew Tutt:

I think with GeparNuevo, I'd completely agree really with what Giuseppe has said. Obviously, we may hear data from other studies with other anti-PD-1 and anti-PD-L1 therapies later in the year, press releases sounding very positive and that might be data that we need to set up and listen to, but we haven't had a chance to scrutinize that yet.

Erika Hamilton:

Absolutely. So before we move on to some of our hormone receptor-positive abstracts, let's briefly just touch on BEGONIA. This was an abstract that looked at triple-negative breast cancer in the first-line setting paclitaxel plus durvalumab. There were multiple arms, but one of the other arms that they presented was a trastuzumab deruxtecan with durvalumab. Obviously, those patients in the trastuzumab deruxtecan arm had to also be HER2-low. So they were both triple-negative and HER2-low, which is a little bit different than the all-comers and paclitaxel-durvalumab. But overall response rates with the paclitaxel combo is 56%, 66% with the trastuzumab deruxtecan. And so, my question walking away from this abstract is certainly impressive response rates there with trastuzumab deruxtecan. It really is a benefit of which one, which there are two agents here. With the data we've seen so far with trastuzumab deruxtecan, you have to wonder how much the immunotherapy is contributing here. Does anyone else have any opinions about this or thoughts when they saw this abstract?

Giuseppe Curigliano:

Well, this is Giuseppe speaking. I was impressed by the results of combining, of course, durvalumab with trastuzumab deruxtecan. Very few patients, so let's advise the people that here we are discussing a very few patients, but [they] provide the rationale to combine, maybe in the neoadjuvant setting, a HER2-positive disease and maybe in some HER2-low immune checkpoint inhibitors with antibody-drug conjugates. I really believe this combination should be explored at  first also in the metastatic setting, because we cannot ignore the risk of toxicity. Don't forget that both the immune checkpoint and the antibody-drug conjugate can give potentially pneumonitis, so we need to better understand the safety. But the potential to combine the both of them is impressive because you can induce immunogenic cell death with the trastuzumab deruxtecan, and then you boost the immune system with the durvalumab. So in my opinion, it's a proof of concept study that the survey further exploration with more patients, both in the metastatic and in the neoadjuvant setting.

Erika Hamilton:

Sara, did you have anything to add here?

Sara Tolaney:

Yeah, I think what I was just going to add, too, is that what is really intriguing is that the benefit was seen both in PD-L1 negative and PD-L1 positive patients. It's hard because I think as everyone's pointed out, these are not randomized data. We don't know what's driving the benefit. And so, is it just that T-DXd works so well in HER2-low disease that you're seeing almost a 70% response rate and that's not going to depend on immunotherapy? Or is there something about the interaction and synergy between an ADC with checkpoint even in a PD-L1 negative patient? So it makes you wonder, is there going to be added a benefit in this setting?

Sara Tolaney:

And so, I think this, as Giuseppe said, does need more work because we can't draw any conclusions here. We don't have any control data to know how T-DXd actually performs in first-line TNBC that's HER2-low, their previous data has been heavily pretreated patients and actually was very limited numbers of triple-negative patients. So in truth, we don't know what the control is here. So hopefully, we'll see more data to be able to flush this out.

Erika Hamilton:

Yeah, absolutely. So maybe not practice-changing, but I think certainly practice-confirming, some of the data we saw from MONALEESA-3 and PALOMA-3 about the addition of CDK 4/6 inhibitors in these studies to fulvestrant and really around overall survival. Giuseppe, do you want to comment on either of these abstracts?

Giuseppe Curigliano:

Potentially, of course, what we have to know is that delivering, of course, in the neoadjuvant setting immuno checkpoint inhibitors, in my opinion, will be the new standard of care in a few weeks from now. I am quite sure, because I know that the data with pembrolizumab will be presented during a virtual session in a few weeks, because it seems that we have a benefit in event-free survival. But also beyond the triple-negative disease, there is also the opportunity to explore this combination also in HER2-positive disease. Many other trials are ongoing, exploring the combination of antibody-drug conjugates with immune checkpoint inhibitors. We will see in the future if this will be practice-changing also in this subtype.

Erika Hamilton:

Thanks. Absolutely. What about the overall survival data for the CDK 4/6 inhibitors in combination with fulvestrant?

Giuseppe Curigliano:

So, I really believe that in this analysis, further analysis, we just confirm that CDK 4/6 inhibitors plus endocrine therapy should be considered a new standard of care. So, I was not surprised at about these results, as I was not surprised about the results in the endocrine-sensitive disease, because also in the study combining with aromatase inhibitors, even if we have, of course, overall survival as a secondary endpoint, there is a clear benefit from the combination of AI plus CDK 4/6 inhibitor. So this confirms that these should be considered as standard of care. I don't believe there will be more space in the future to consider endocrine therapy alone in this patient population. What is the open question how to position the oral SERDs in combination with CDK 4/6 inhibitors for the future. Here, many abstract has been presented also by you and this is the major point to discuss here, I believe.

Erika Hamilton:

Yeah, I absolutely agree. SERDs was on my agenda to get to. I think we saw at least four or five presentations of novel endocrine agents. I guess maybe this is a good time just to mention the VERONICA study. It was a study of fulvestrant with or without venetoclax, the Bcl-2 inhibitor. We'll keep this part short, but suffice it to say it was a negative study. No benefit in clinical benefit rate, no benefit in progression-free survival and really more toxicity as well. So that's something not to do, but I completely agree with you, Giuseppe, that post-CDK 4/6, we really need a better agents for AR-positive disease. It looks like SERD really is where it holds a lot of promise. Sara or Andrew, any comments on this? Where you think we're going to end up using SERDs, et cetera?

Andrew Tutt:

Well, if I could just comment on the VERONICA study for a moment, because I think I would have to say, it is negative. I don't think one should say anything other than that. I was very disappointed that that was the case, because I think that there is more to understand. I think there was a good rationale. I think we need to understand what it is about AR-positive breast cancer that leads us to fail to kill it in the way that we can in the AR-negative forms of the disease.

Andrew Tutt:

I feel sure that if we just persist in trying to understand the underpinning biology of upregulation of those Bcl-2 family members, and there are a number of them better, and I think Jeff Linderman had done that very well in his prior work, then I think there will be subpopulations of this big disease area, this big subset that we can do better for with agents in this class. So I hope this wasn't a flash in the pan, where we had a great idea, did one test of it, weren't gratified instantly and gave up. I think we need to do more think deeply reset and see if we can move forward. I feel sure there is more to do here.

Erika Hamilton:

Yeah, I completely agree with you. I think it's interesting to think back to several years ago when we thought Rb was going to be the story post-CDK 4/6, and it really looks like the mechanisms of resistance and what changes in tumors is quite varied. So just like how we talk about triple-negative breast cancer not being one disease, I think post-CDK 4/6 AR-positive is not one disease either. So ultimately we're probably going to do better if we fractionate this population out a little bit.

Andrew Tutt:

Yeah, exactly.

Erika Hamilton:

Sara, what do you think about the oral SERDs? Where are you excited for them? Where do you think we'll end up using them?

Sara Tolaney:

Yeah, I've been very excited about them. I think we've been a little disappointed about the bioavailability of fulvestrant, and so we've been trying to do better. But I think the challenge is that the data that we have for the search today is really mostly from phase one and phase one expansions. And so, the populations that have been evaluated have really been very heterogeneous. And so, I think it makes it a little challenging to know how actually does an oral SERD compared to fulvestrant. We don't yet have the data from the randomized studies to know that. I think there's every reason to believe they are at least as good, if not better, but I think we need to see those data.

Sara Tolaney:

There are some interesting emerging side effects from some of these drugs again. Or generally, from my experience, they've been well tolerated, but there are some interesting side effects that have emerged, including some bradycardia, visual disturbances. And so, I think I want to see the larger data sets. I think we're hoping soon we'll have potentially the randomized Sanofi data with amcenestrant, the elacestrant randomized data versus endocrine choice from EMERALD. So I think those data should be emerging soon to help us better understand.

Sara Tolaney:

But I think to your point earlier about where will they go, I know there are many first-line trials comparing SERD, CDK to AI CDK. While I think it's an important thing for us to study, I'm also a little cautious about it, because we saw data from PARSIFAL that had suggested in endocrine-sensitive patients, maybe your choice of endocrine therapy doesn't matter with the CDK 4/6 inhibitor. And so, I think we need to learn more. I think we're hoping they may prevent emergence of ESR1 mutations and maybe they're going to help extend PFS, but I think we need to know. I know there's a lot of interest in also moving these agents into the adjuvant space and how we do that best, I think we'll need to see, but I'm very hopeful about them, but again, awaiting the randomized data.

Erika Hamilton:

Yeah, absolutely. I think you bring up a good point, too, about comparing apples to apples, right? Even the four studies that were presented at ASCO range from practically first and second line only, and no prior CDK, and the two palbo combinations with rintodestrant and amcenestrant to heavily pretreated with H3B, et cetera. Any comments from others on this class of agents or what you're excited about?

Giuseppe Curigliano:

I would like to comment on amcenestrant data because finally, if you look at impairments of activity, when you combine with palbociclib, you have something like 35% response rate and the clinical benefit rate of 70%, and no grade three, four toxicity. So this is an important observation. So in the context of further development of these agents, should we explore them in a sequential treatment or should we move them directly in the adjuvant setting? Because an oral SERD has been developed primarily in order to overcome the resistance in ESR1 mutation. We know they are tempting to pass to move a SERD the adjuvant setting. So I really believe that the new trials that are coming in the adjuvant setting will give the response. Because in my opinion, I am not looking to a strong activity in the metastatic setting. I would like to have a more active agent in the adjuvant setting with these new agents. The opportunity to deliver a SERD orally, it's a huge opportunity for our patients in the adjuvant setting.

Erika Hamilton:

Yeah, absolutely. I may direct another question to you, Andrew. I also had the opportunity to see Jennifer Litton's abstract on neoadjuvant talazoparib. Obviously, a small subset of patients. It was about 48 patients, but without chemotherapy and 24 weeks of talazoparib delivering a pathologic complete response rate in about 46%. I mean, I thought that was really astounding, especially for patients with BRCA mutations that may be our younger patients and have more time to live with the side effects of chemotherapy, this idea that could we spare them some chemotherapy? What did you think about that study? I thought it was a bit of a shame that we're not going to have more data of these patients follow long term.

Andrew Tutt:

Yeah. I think I also found that a fascinating abstract and presentation and great work. I think, again, it's a shame and she was... Jennifer was very clear that the reason things stopped was a commercial business decision by the sponsor and not for any other sort of more scientific reason. I think we've got very interesting data from that study and also actually from GeparOLA, different context, but the use of olaparib in a combination with chemotherapy with paclitaxel deescalating the platinum, if you see what I mean, replacing it with olaparib. Both of which raised the question as to whether or not we can modify, remove, or modify chemotherapy in BRCA mutation carriers with the use of PARP inhibitors ahead of surgery. I think there are a number of trials that people will now wish to design testing that, both of those questions instead of chemotherapy or as a component with chemotherapy, removing perhaps some of the more toxic elements. The door is now open with proof of concept for that as a result of that work.

Andrew Tutt:

I have some concerns about talazoparib's impact on bone marrow and transfusion requirements and things which seem to be greater than we're experiencing with other PARP inhibitors. And so, there are effects on young women that are not insignificant if you're going into lower risk populations, but I think we do need to do some of these studies with PARP inhibitors in that setting and see if we can deescalate the therapy in the lowest risk groups, and perhaps those groups that were not included in OlympiA. There were lower risk patients excluded from OlympiA, who we could potentially be looking at a PARP inhibitor strategies for instead of chemotherapy. I know a number of groups are looking at those designs now.

Erika Hamilton:

Yeah, I thought that was actually a large theme at ASCO this year, was this right sizing the therapy for the patient, whether it's deescalation or escalation with the addition of PARP inhibitor, et cetera. But we also saw some data without chemotherapy with two HER2-targeted agents early on. And then we also saw an abstract including a lot of advocates about talking to physicians about dose reductions and really making sure that quality of life is paramount in everyone's mind as well. Sara, did you have any comments on that? I really think theme over the past several years that we have a lot of agents in our tool bag, so to speak now, but really getting smart about who needs which one and making sure that we right-size it for each patient in front of us.

Sara Tolaney:

I think this is so critical because I think as we're getting better and better drugs that have more efficacy rather than just always adding on, we need to think about how to subtract potentially to maintain efficacy, but diminished toxicity. I think that is a huge theme, just like Andrew was talking about, the NEOTALA study, right? Can we potentially replace chemotherapy with a targeted drug now that we can see that it has efficacy? It's going to take time to sort through how to do that because we do need to preserve efficacy, but I think this is our movement. As we learn more about biomarker predictors of response, as we get better agents, I think we're going to be able to move in this direction, which is, I think, really exciting times.

Erika Hamilton:

Yeah, absolutely. So in the last few minutes that we have, maybe we'll go around the table and each person leave us with a parting word, something they're excited about seeing in the future or something we didn't touch on that you think would be remiss not to mention. Andrew, how about we start with you?

Andrew Tutt:

Well, thank you for that opportunity. Well, while I would want to strongly point out that the results that the group that I represented presents around OlympiA are as relevant to hormone receptor-positive breast cancer as they are to triple-negative breast cancer, I do think it is fantastic that within this form of the disease that is defined by its negativity, by what it isn't, that I think we now have a reason to seek a positive patient selection biomarker through genomic genome sequencing of the germline. We should really think about doing that much more and then designing studies that go beyond this for that population of patients we have a positive biomarker in, while remembering that we probably ought to sequence a lot more patients who have hormone receptor-positive disease, because we've kind of forgotten that they not infrequently have germline mutations.

Erika Hamilton:

Great. Giuseppe, how about you?

Giuseppe Curigliano:

I completely agree with Andrew, the most important data where the data of OlympiA that we addressed a lot, but I also believe we need to consider all the deescalation trial. So it was of interest the trial from the Chinese group, the size of trial in which has been compared that trastuzumab plus endocrine therapy versus trastuzumab plus chemotherapy in a population of patients that were HR-positive, HER2 positive. Of course, the study was underpowered to the most later benefit in overall survival, not the progression-free survival was quite similar. So I believe in the future, we need to better identify those patients who can do a deescalation in the metastatic setting, also in the adjuvant setting. If you look at the data of ADAPT-ER in which a short exposure to endocrine therapy can modify also the biology of a cancer that may have a better prognosis. So, decrescendo will be the future. In this ASCO, we had escalation trial, like the OlympiA, for very well-defined according to precision medicine subgroup of patients, but also deescalation trial in order to guarantee a better quality of life to our patients.

Erika Hamilton:

Great. Absolutely. Well said. Sara?

Sara Tolaney:

I think just along those themes, I very much agree. I think we're really moving towards personalization. So whether it's using germline testing to select patients for therapeutics or genomic alterations, or even I'd see markers now for ADC selection, potentially, I think this is our movement forward, is how can we best personalize care to improve outcomes and decrease toxicity. I think we saw so much of that at ASCO this year, which was exciting.

Erika Hamilton:

Absolutely. I think I'll build upon that theme, but I also think access is a big issue, whether that's access to PD-L1 testing, access to BRCA testing. There's been recent data that certain minority groups are actually offered a BRCA testing less. So I think that's something that we're going to have to be very cognizant as a community to change to make sure that all patients have access to the same exciting therapies, regardless of where they live or their background, ethnicity, et cetera. On behalf of VJOncology, I'd like to thank you guys for listening, tuning in, and having this chat with us, and also, thank Sara, Andrew, and Giuseppe for joining me. Thanks so much.

Andrew Tutt:

Thank you.

Sara Tolaney:

Thank you.

Giuseppe Curigliano:

Thank you.

Disclosures
Sara Tolaney:

Dr Tolaney received honorarium for consulting/advisory board work from: AstraZeneca, Eli Lilly, Merck, Novartis, Nektar, Nanostring, Pfizer, Genentech/Roche, Immunomedics/Gilead, BMS, Eisai, Sanofi, Odonate, Seattle Genetics, Puma, Athenex, OncoPep, OncoSec, OncXerna, Daiichi-Sankyo, CytomX, Certara, Mersana Therapeutics, Chugai Pharma, Ellipses Pharma, 4D Pharma, Infinity Therapeutics, Beyond Spring Pharma.

Dr Tolaney received research support/grants (all payment to institution) from: AstraZeneca, Eli Lilly, Merck, Novartis, Nektar, Nanostring, Pfizer, Genentech/Roche, Immunomedics/Gilead, BMS, Eisai, Sanofi, Odonate, Seattle Genetics.

Erika Hamilton:

Dr. Hamilton discloses research funding (payable to institution only, no personal funds) from : OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs.

Dr. Hamilton discloses consulting/advisory role payments (to institution only, no personal funds accepted) from: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen.

Giuseppe Curigliano:

Dr. Curigliano reports personal fees from Roche, Pfizer, Novartis, Lilly, Foundation Medicine, BMS, Samsung, Astra Zeneca, Daichii Sankyo, GSK, Seagen; non-financial support from Roche, Pfizer; grants from Merck; other from Ellipsis

Andrew Tutt:

Support typeName all entities with whom you have this relationship or indicate none (add rows as needed)Specifications/Comments(e.g., if payments were made to you or to your institution)
Time frame: Since the initial planning of the work
All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) No time limit for this item.Breast International Group Main study Grant from AstraZeneca and Merck Sharp & Dohme CorpFinancial support to my academic & hospital institutions for Admin Support costs associated with UK Chief Investigator and Local PI role and local site cost
Breast International Group Main study Grant from AstraZeneca and Merck Sharp & Dohme CorpTravel expenses related to trial related travel expenses payments to Institution through Breast International Group for Steering Group meetings at ASCO and San Antonio Cancer Conferences associated with BIG Study Chair role and conduct of Olympia trial
AstraZeneca and Merck Sharp & Dohme CorpEditorial support for the final draft was provided by Aaron Borg, PhD and Helen Stimpson, PhD from Oxford PharmaGenesis Ltd funded directly by AZ and MSD. No payment to me or my Institution
Time frame: past 36 months
Grants or contracts from any entity (if not indicated in item #1 above).Breast cancer Now Charity(BCN)Peer Review Grant Programme Grant funding to Institution for Andrew Tutt to study homologous recombination deficient breast and other cancers. BCN receive payments entirely independent of A Tutt through Institute of Cancer Research from AstraZeneca related to PARP inhibitor associated patents outlined below
CRUKGrant funded to Institution study homologous recombination deficient breast and other cancers, CRUK receive payments through Astrazeneca related to PARP inhibitor patents / personal fees / Honoraria associated with function as Deputy Chair and reviewer for CRUK clinical research
Royalties or licensesInstitute of Cancer Research (ICR)AstraZeneca pay royalties to my employing Institution (Institute of Cancer Research) associated with a Patent on use of PARP inhibitors in DNA deficient cancers, licensee - Astrazeneca.

I have received payments to Andrew Tutt personal account and Research Account from Institute of Cancer Research through ICR rewards to Inventor’s scheme. These have all been submitted to the OlympiA Trial Sponsor AstraZeneca on FDA Disclosure form and to ASCO COI Portal.

I contributed to original scientific work that led to a patent on use of PARP inhibitors in DNA deficient cancers, licensee – Astrazeneca, while working at the ICR in the period 1997-2005.

I received intermittent payments as a result from the Institute of Cancer Research Rewards to Inventors scheme. As far as I can recollect these began in 2009 and are listed below. Some of these have been paid into my personal account by ICR via Bank Transfer, others have been paid into an ICR regulated Research Account. It is anticipated that a payment will be made in 2021 that may be between £30,000 and £40,000 that I declare as this is likely to be in excess of the $25,000 figure referred to under item 5 of the FDA disclosure form.

It is possible that studies that I currently have a leadership role in as Chief Investigator could contribute data that leads to financial benefit to the patent holder Astra Zeneca that would lead to benefits to my Employer the Institute of Cancer Research and that further payments would then be offered to me through the ICR Rewards to Inventors Scheme based on the original patent.

I also declare that the Research Charity Breast Cancer Now, to whom I apply for Peer Review Grant Funding, also receive payments under the same Patent provisions.

Although I make this declaration, I do not believe that the above constitute a Conflict of Interest for my role as Study Chief Investigator as Phase III studies that could extend Olaparib marketing authorisation, such as OlympiA are regulated and overseen by an independent academically lead Trial Steering Committee, have 3 additional co-PIs, an independent statistical team and and an entirely independent and academically lead data monitoring and safety committee (IDMC).
Consulting fees
AstrazenecaPersonal fees for Advisory Board
PfizerPersonal fees for Advisory Board
Prime OncologyPersonal fees for Advisory Board
ArtiosPersonal fees for Advisory Board
Merck SeronoPayments to my institution
VertexPersonal fees for Advisory Board
MD Anderson Cancer CentrePersonal fees for Advisory Board
InbiomotionPersonal fees for Advisory Board
Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational eventsSABCSSymposium payment for participation
MedscapePersonal fees / speaker for a video series tentatively titled "Understanding the Rationale for PARP Inhibitors and their Combination with Immunotherapy in the Treatment of Various Solid Tumors
Payment for expert testimonyCRUKPayment for expert panel and Vice Chair Grant Review Committee role
Support for attending meetings and/or travelAstrazenecaTravel expenses related to trial related travel expenses payments to Institution through Breast International Group for Steering Group meetings at ASCO and San Antonio Cancer Conferences associated with BIG Study Chair role and conduct of Olympia trial
PfizerTravel expenses to conference and Advisory Board
Patents planned, issued or pendingAstrazeneca licenseeAstraZeneca pay royalties to my employing Institution (Institute of Cancer Research) associated with a Patent on use of PARP inhibitors in DNA deficient cancers, licensee - Astrazeneca.

I have received payments to Andrew Tutt personal account and Research Account from Institute of Cancer Research through ICR rewards to Inventor’s scheme. These have all been submitted to the OlympiA Trial Sponsor AstraZeneca on FDA Disclosure form and to ASCO COI Portal.

I contributed to original scientific work that led to a patent on use of PARP inhibitors in DNA deficient cancers, licensee – Astrazeneca, while working at the ICR in the period 1997-2005.

I received payments as a result from the Institute of Cancer Research Rewards to Inventors scheme. As far as I can recollect these began in 2009 and are listed below. Some of these have been paid into my personal account by ICR via Bank Transfer, others have been paid into an ICR regulated Research Account. It is anticipated that a payment will be made in 2021 that may be between £30,000 and £40,000 that I declare as this is likely to be in excess of the $25,000 figure referred to under item 5 of the FDA disclosure form.

It is possible that studies that I currently have a leadership role in as Chief Investigator could contribute data that leads to financial benefit to the patent holder Astra Zeneca that would lead to benefits to my Employer the Institute of Cancer Research and that further payments would then be offered to me through the ICR Rewards to Inventors Scheme based on the original patent.

I also declare that the Research Charity Breast Cancer Now, to whom I apply for Peer Review Grant Funding, also receive payments under the same Patent provisions.

Although I make this declaration, I do not believe that the above constitute a Conflict of Interest for my role as Study Chief Investigator as Phase III studies that could extend Olaparib marketing authorisation, such as OlympiA are regulated and overseen by an independent academically lead Trial Steering Committee, have 3 additional co-PIs, an independent statistical team and and an entirely independent and academically lead data monitoring and safety committee (IDMC).
Participation on a Data Safety Monitoring Board or Advisory Board
AstrazenecaPersonal fees and Payments to my Institution for Advisory Board
PfizerPersonal fees for Advisory Board
Prime OncologyPersonal fees for Advisory Board
ArtiosPayments to my institution for Advisory Board
Merck SeronoPayments to my institution for Advisory Board
VertexPersonal fees for Advisory Board
MD Anderson Cancer CentrePersonal fees for Advisory Board
InbiomotionPersonal fees for Advisory Board
GileadPersonal fees for Advisory Board
GE HealthcarePayments to my institution for meeting
Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaidCRUKVice Chair on Experimental Medicine and Clinical Research Committees - Paid
OlympiAGlobal Academic Study Chair for Breast international Group – No Payments
Stock or stock optionsInbiomotionStock option
Receipt of equipment, materials, drugs, medical writing, gifts or other servicesPharmaGenesis LtdEditorial support for the final draft of this manuscript was provided by Aaron Borg, PhD and Helen Stimpson, PhD from Oxford PharmaGenesis Ltd funded directly by AZ and MSD. No payment to me or my Institution
Other financial or nonfinancial interestsMERCK KGAATo Guy’s Hospital Local site trial support costs associated with an DNA repair inhibitor clinical trial
Roche / GenentechDrug Provision support for pre-clinical research at ICR
Myriad GeneticsFinancial support for research costs associated with conducted of ICR/KCL Sponsored TNT Trial
MedivationFinancial support for research at ICR
ArtiosFinancial support for wet lab research on DNA repair conducted in my Division at ICR

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