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Dr. Harbeck: Hi. Welcome to our podcast on the Current Application of PI3 Kinase and AKT Inhibitors in Patients with Metastatic Breast Cancer: Areas of Agreement and Controversy. My name is Nadia Harbeck. I am the Director of the Breast Center at LMU University Hospital in Munich, Germany. I am very glad to be here today with Dr. François-Clément Bidard from Paris. François, do you want to introduce yourself?

Dr. Bidard: Hello, Nadia. François-Clément Bidard here. I am a Medical Oncologist. I am working in Paris at Institut Curie , where I lead clinical research on breast cancer. I am also the Vice President of the French Breast Cancer Group. So, happy to be here with you to discuss the use of PI3K and AKT inhibitors.

Dr. Harbeck Yes, there is a lot to discuss because we just started to use the more modern compounds and there is new trials coming up. So, it is a very fitting time to have a discussion. If you look at the patients with the primary resistance to neoadjuvant or adjuvant therapy and the first-line therapy, what are your standards and how do you deal with that?

Dr. Bidard: That is a good question to start with. Basically, we will divide the population, so the ones that are considered as having a disease, which is resistant to endocrine therapy. Of course, we will divide it following what has been initially developed in the ABC guidelines, which is trying to divide the primary endocrine resistance population. So, patients who are relapsing during the first 2 years of adjuvant endocrine therapy or progressing during the first 6 months of the first-line with CDK4/6 inhibitor combined with AI in patients with metastatic breast cancer.

We have this core population, small population of patients with primary resistant endocrine breast cancer. Then we have the secondary resistant which is patients who are relapsing after 2 years on adjuvant endocrine therapy and up to 12 months after the discontinuation of endocrine therapy. Of course, also in the metastatic setting, patient who would experience a disease progression during the first-line with AI and CDK4/6, but after the first 6 months on treatment. Basically, we have these 2 populations which are considered as being somehow endocrine resistant. Then the key question is, what to offer for this patient?

First thing is we have to consider endocrine therapy. Then that is the first choice, and that is something we could discuss after is, should we go with the next line with an endocrine therapy agent or do we have to introduce chemotherapy/ADC? That is a question I am not sure we have the right answer but we could discuss that later.

Ant then if you choose an endocrine therapy-based treatment, then you have to think in terms of combination. What we know is that single-agent endocrine therapy is unlikely to work for a long time in most patients at least. So most of the time, the second-line will be made of a combination between an endocrine therapy agent and something else, which is supposed to increase the efficacy.

What is this something else? It could be multiple agents and so we could have sometimes rechallenge with CDK4/6 inhibitor. But what is most interesting is that in that setting of patient with endocrine resistance, what has emerged is the idea of targeting PIK3CA pathway, which drives the resistance to endocrine therapy in about half of the patient population. That is what I would say. When it comes to specific agents, maybe, Nadia, you could remind the people who are listening, what are the current agents we have to target this pathway?

Dr. Harbeck: Yes. Well, you outlined it nicely with the endocrine resistance. That is the only time point when we actually test for biomarkers in the first-line setting is if you have a patient that comes very quickly on or within the first year after adjuvant therapy. That is the time when we would test PIK3CA mutation. If the patient has a mutation, we would put her on the triplet combination, inavolisib-palbociclib and fulvestrant.

I do not know whether that is available in France yet, but in Germany we have just started, so we would be using that. It is not that many patients yet. So, I cannot tell you how effective this is, in particular if the patient came from an adjuvant CDK4/6 inhibitor, but that is the only time when we would test in the first-line setting. Otherwise in the first-line setting, we would go for CDK4/6 inhibitor with an AI and then test in the second-line setting.

I know that you have done this outstanding work with your own PADA-1 study, but also with the SERENA-6 study. You would probably start already testing under the first-line CDK4/6 inhibitor plus AI, at least for ESR1 mutation. Is that right?

Dr. Bidard: Yes, that is a good point. Yes, we have an interesting ESR1 mutation. Obviously because we know the driver resistance to AI, and we also know that they are very frequent, about 40% of patients. What is interesting is the only driver part of the resistance to AI and they are not driving resistance to other SERDs.

Back to the time of testing is very important, too, because the second-line now we have in France. At the moment, we do not have access to capivasertib in the second-line. We are still awaiting, but we do have an access to inavolisib in first-line. This is granted through an early access protocols. So, it is very interesting for us to also have our first real life patient treated with inavolisib.

What is interesting and what could differ from country to country is the way to test the patient population. What we do? We have 2 different settings here. We have this first-line for patients who are relapsing on adjuvant endocrine therapy. For this patient, what we know is that disease is likely to be quite aggressive. This patient have symptoms during the adjuvant treatment. Of course, we need to put them on treatment very quickly. So, it means that we need a fast turnaround time, very short turnaround time to get the biomarker results. And what we do mostly is to use ctDNA, which is non-invasive. And at my site, we have a turnaround time of about 10 days to two weeks to get the result, which is acceptable. With ctDNA, we know we will be able to capture most of the tumor with a PIK3CA mutation. We know PIK3CA is easy to detect, but not all patients may have enough ctDNA levels in their blood, but most patients will have enough ctDNA levels to catch this mutation. Catching this mutation would allow us to put the patient on inavolisib plus palbociclib plus fulvestrant. That is what we are currently doing. When we have more time, which is patients that have an endocrine-sensitive disease, so they are treated with first-line AI plus CDK. What we do at my site is that we test during the first-line. We have time to test the primary tumor or any biopsy. We would do NGS on tissue, and that NGS would cover not only PIK3CA but will cover other mutations such as PTEN and AKT.

We would be able to determine before the patient experienced disease progression whether they would be eligible for second-line treatment, keeping in mind that at the moment we do not have access in France to capivasertib. I think you have access to capivasertib in Germany, do not you?

Dr. Harbeck: Yes. That would be our second-line choice, where we follow the ESMO guidelines basically and we have access to the drugs that are listed there. In those patients that are endocrine sensitive or where we go for CDK4/6 plus AI in the first-line setting, we would then test for PIK3CA mutation, AKT pathway alterations and ESR1. We mostly do this in the liquid biopsy at that particular point. If we just test for PIK3CA mutation in the first-line setting to see whether there is inavolisib indication, we may resort also to the tissue that we just collected to, to verify the metastasis. We can do both for PIK3CA because it is a driver mutation more than it is not acquired. But for ESR1, I completely agree.

Then testing in the second-line basically would then tell us whether we have a patient that is eligible for an oral SERD. So far in Europe, we only have elacestrant available in Germany. We have both elacestrant and imlunestrant approved in Europe, but not available in the markets yet with regard to imlunestrant.

Then we check whether we have a PIK3CA mutation, which is the most frequent also in the AKT pathway, or AKT or PTEN alteration, then go for capivasertib plus fulvestrant. We do not use a PI3 kinase inhibitor in the second-line setting because alpelisib is not available in Germany, and the toxicity pattern I think is more favorable for capivasertib. That would be my second-line choice.

Then if you do not have an alteration, we can still use everolimus. It is old, but it is still good if you want to go for another line of therapy. But something you said, let me go back to the first-line inavolisib. I just wanted to ask you, what would you do with patients? Because I do not think we have patients yet that have progressed on this triplet combination. Would you then take them right away to chemo or would you still test for ESR1 mutation?

Dr. Bidard: Actually, we will have this clinical setting quite soon because we started to have patients in real life at my institute, so we started inavolisib, but it is very recent. So, they have not yet progressed. What we know is when it comes to the PFS, PFS with inavolisib was quite long. It was 17 months at least in the trial. We will see how it goes with that. That is more than one year, almost one year and half. We will see our first patient fair under the combination in real life. I think that these patients have some endocrine resistance. They relapsed on adjuvant endocrine therapy. Obviously, at that time when they progress, we will switch to chemo.

Yes, some patients may be eligible for a further line of endocrine therapy, but what we know is that they are not very likely to develop an ESR1 mutation because they have been treated in first-line with fulvestrant. We know that ESR1 are more likely to appear when patients are exposed to aromatase inhibitors.

There will be, of course, some ESR1 mutation but not that frequent. I am not sure we have any data to show that there is a strong activity with any oral SERD given as a second-line after a PI3K inhibitor plus CDK4/6 after relapse in the adjuvant setting. Obviously, this patient at time of progression will have very aggressive disease and will likely be treated with chemo. That is what I do.

Of course, it will depend on the clinical setting. We will have to discuss it. Obviously, I will go to chemo. That is also part of the discussion is when to balance the choice between chemotherapy, which could also be given first-line and other endocrine-based treatments when a patient relapse on adjuvant endocrine therapy. I know that we are sometimes proposing chemotherapy as a first-line option. Chemotherapy could include oral agents such as capecitabine. We could also consider T-DXd. At the moment, we do not have access in France to T-DXd as a first-line chemo, like in DESTINY-Breast06, but we are using it mostly in the second-line.

We would obviously request HER2-low assessment or reassessment or rebiopsy. That is something we have to keep in mind because it is balancing between attractive endocrine therapy-based regimen, but also we have very attractive chemotherapy or ADC regimens. That could come with a very interesting efficacy. I do not know, at your site, how do you balance for patients? How do you drive your decision? Is it performance status or site of metastasis, or do you put everyone on endocrine therapy?

Dr. Harbeck: In the first-line, we would try to give endocrine-based therapy to everybody. We do not do this on your approach. We would always start with the CDK4/6 inhibitor unless we need the triplet combination as discussed before. There is hardly ever patients where we feel that there is so much disease burden and it is so aggressive that we should start with chemotherapy. There were very good review in Germany from the Pregnant network showing that that is probably 10% to 15% of all patients and the rest will go down the endocrine-based route.

We also would try to give more than one line. I completely agree with you that we do not know what happens after the triplet inavolisib-palbociclib and fulvestrant, because we do not have patients that have progressed and we did not participate in the registration trial. So, we are not sure, but I could foresee because we have covered pathways. If it is a very rapid progression, we would definitely put her on chemo. If it is more like a slow progression or so, then maybe we would test for ESR1 if she has had ESR1, an aromatase inhibitor in the adjuvant setting, maybe there is a mutation. We would do that. When it comes to chemo, we are tempted to give T-DXd first-line because the data is very compelling for DESTINY-Breast06. We just had a case like this in the tumor board and was a patient that was actually a little bit frail, but we were asking maybe capecitabine, maybe T-DXd. But the patients do not get better with the next line of therapy. So it is always good to give T-DXd maybe in the first-line as a chemotherapy, because patients may not have a good enough constitution that they can have it second or third-line. So, we are leaning towards T-DXd.

Other than that, we are trying to give at least 2 lines of endocrine-based therapy. We would also maybe try a third-line if there is a mutation that we can target. We usually do the capivasertib plus fulvestrant if there is a PIK3CA mutation in the second-line setting, but also an oral SERD by itself. If there is any ESR1 mutation in a very slowly progressing disease, maybe a good option.

We also know from the ELEGANT trial that if you give like the oral SERD as a single-agent too late, maybe a third of the patient will not benefit anymore and progress rapidly. That would be the point then when we would definitely switch for chemo.

Sometimes we have these patients with these co-mutations. Then there is always a big discussion in the tumor board, what do you do? What would you do if you have ESR1 mutation and a PIK3CA mutation?

Dr. Bidard: Yes. That is, of course, a question that is very recurrent. From the data first, we know that we have 40% of ESR1 mutation at time of progression under AI. We also have 40% of patients with PIK3CA mutation and up to 50% if you take into account AKT and PTEN. If you combine, it a PIK3CA and ESR1, so it is 40% by 40%. At the end, it is between 15% to 20% of the patient population. There is no mutual exclusivity or something.

It is really doing the math. 15% to 20% of the patient population will have this double mutation. Then the question is, of course, as you pointed out, what should we target? Of course, we are all awaiting trials with oral SERDs combined with agents that are targeting PIK3CA or ATK. At the moment, we have to choose between single-agent oral SERD, imlunestrant, when available, or elacestrant. Or fulvestrant, which is the old SERD combined with an ATK inhibitor or PI3K inhibitor.

Of course, then when you look at the PFS and you could look at the evidence, the PFS might look a bit longer with PI3K/AKT inhibitor compared to oral SERD, but there was some difference in the population. It is not so easy to make a definitive call in terms of efficacy for PFS.

When it comes to overall survival, at the moment, there is only one trial that has shown benefit in terms of overall survival, and that trial is INAVO120. Which means in the context of patients relapsing on adjuvant endocrine therapy, even though there is an ESR1 mutation, definitely in terms of level of evidence, I would go for inavolisib. Then the next question, when you really have a choice and you do not know what to choose, then, of course, you have to adapt your choice to the patient you are facing. Then it comes to the different side effects. Here I would say that oral SERD are overall very well tolerated when we have to face real toxicities with agents that are targeting PI3K or AKT. We made a lot of progress since the first generation inhibitors, such as buparlisib (BKM120) and pictilisib (GDC-0941), which were too toxic to actually make it to the market. We had the second-generation inhibitor, which were more selective toward PI3K-alpha. These include alpelisib. We also had taselisib in SANDPIPER.

Alpelisib was still available in the US, but approved in Europe and they are not reimbursed. At the end, it is not available anymore in Europe. Now we have like selective inhibitor of PI3K-alpha.

With inavolisib, the toxicity is getting better, but still we do have two thirds of patients who will experience hyperglycemia. We have skin rash, we have diarrhea. We have stomatitis and it could be also some dry eye effect something. These are toxicities that need to be discussed with the patient and you have to adapt. The way to manage these toxicities is very important because we will all have a training curve, especially for clinicians who did not participated to our registration trials, it will be our first-hand experience.

It is something that a lot of education is needed. For the audience, I just want to mention that there is an excellent paper that has been published in the very first months of 2026 and published in ESMO Open by Komal Jhaveri (Jhaveri KL, Iyengar NM, Turner NC, et al. Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer. ESMO Open. 2026;11:105936). You could find it on PubMed, it is open access, and it is just about all the toxicity of PI3K inhibitors, but also AKT inhibitors and how to manage it. That is very important.

You will have a very comprehensive table about the different action to take. Just very briefly, they will say what kind of assessment you should do as baseline, like glycated hemoglobin and so on. What you could do in terms of preventive measure whenever you want to put a patient on metformin or not and so on, which depend on the drug. It depends on the context. This is something that is very basic, but it is needed. You need to know that before initiating a treatment with inavolisib, for example. It is kind of guidelines about the monitoring during treatment and also what to do in case of adverse events. I would encourage the audience to refer to that article. Very easy and also very important, because we are not endocrinologist. Diabetes, honestly, I do not know what to do most of the time.

When you are working in a large university hospital, you could always find an endocrinologist walking by in the corridor. It could be that you are working in a smaller private practice and you do not have endocrinologists that are working around. So it is very important to keep that in mind.

Final answer to your question is a balance between oral SERD single-agent and agent targeting PIK3CA. I would make the call based on the level of evidence. Overall survival is in favor of using inavolisib. Then second is about tolerability and whether the patient is overweight that could lead to higher toxicity of PI3K targeting agents.

I remember when we used alpelisib in France, quite a long time ago, with the very first patient it was a bit tough. Then it was better for the next one. We have to educate our community to how to manage and we have to educate the nurse and the general practitioner as well. That is part of finding the appropriate patient for this agent.

I do not know how do you do about whether you would send your patient to an endocrinologist to manage diabetes or whether you would prescribe metformin or do it yourself, Nadia? What would you do with this hyperglycemia, which is the most common side effect for these agents?

Dr. Harbeck: Yes, we usually team up with the diabetologist. Maybe some patients already have somebody who can help us there, because in Germany, a lot of the breast cancer doctors are trained gynecologists and we know about diabetes from treating pregnancy and diabetes, but it is not something that we do so often.

It is a network and you are very right in pointing that out that we have to create this network for these new agents. That is true also beyond the PI3 kinase inhibitors. It is something that everybody has to figure out for themselves. The nice thing is that when new agents come along, you already have these connections. I found that the toxicity gets better and better with these new developments. For example, we participated in the CAPItello study, and I could not tell after the first cycle which arm my patient was in. That is always a good sign for a new drug that the toxicity is actually very manageable. You mentioned alpelisib has completely probably disappeared from our management because we now use capivasertib in those patients.

There will be a trial, the INAVO121, just directly comparing inavolisib with alpelisib. We will see how these newer generation of PI3 kinase inhibitors does not just with efficacy but also with safety. That is one of the trials I am looking forward. It is fully recruited, so we will have that soon.

There was one thing that I was intrigued, and I am also participating in the INAVO122 trial and it is about inavolisib in HER2-positive breast cancer. You may ask why that? There is this nice paper by Sibylle Loibl showing that PIK3CA mutations in the early-stage setting in mostly HR-positive/HER2-positive disease is actually a predictor of poor pCR in those patients.

I mean, they are a resistance factor in the HER2-positive setting. It is a very interesting trial where we have an induction with the CLEOPATRA regimen. Then for the maintenance patients where PIK3CA mutation get randomized to inavolisib in addition to the regular maintenance versus placebo control. That is an interesting more outside-the-box approach to PI3 kinase inhibitors. I am really curious to see what the data will look like.

You overlook the scene quite well because you are also participating in a lot of these targeted endocrine trials. Are there any other newer, even better developments in the PI3 kinase/AKT pathway inhibitor fields that you are excited about?

Dr. Bidard: Yes. There are like many developments. Of course, we have inavolisib, which is a more selective but still like ATP mimetic drug, which is a drug that will block the enzyme. It is a kind of a poison. That drug, as you mentioned, you have a lot of trials investigating HER2-positive metastatic breast cancers. There is also INAVO123, which is currently targeting the endocrine sensitive population. It is basically palbociclib or ribociclib plus AI plus or minus inavolisib.

Obviously, inavolisib will continue its development because of its favorable toxicity profile compared to other PI3K inhibitors. What is also interesting is the progress in chemistry. I mentioned like first generation, like they were too toxic. They never made it to the approval.

Then we had the second generation, like alpelisib like a bit more specific for the mutant form. Then now we have something that is like more specific with inavolisib. What are the progresses in chemistry? Now we have allosteric inhibitors. Allosteric inhibitors are compounds that are inhibiting the mutated form of PI3 kinase. They are inhibiting it not by binding to the enzymatic part to the enzymatic pocket, but they are binding somewhere else.

These new agents are interesting because they are extremely specific for the mutant isoform. At the moment, we do not have any of these agents in clinical routine. It is not for today, but just for the people who are listening, it is interesting to keep in mind that chemistry is making progresses.

We have 2 main compounds that are being developed. One is developed by Relay Therapeutics and the name is zovegalisib. It is currently in the second-line trial with the ReDiscover-2 trial. We also have an allosteric inhibitor developed by Lilly whose name is tersolisib. Tersolisib will be investigated directly in first-line. It is interesting to see like it is always about combination with endocrine therapy and more and more combination also with CDK4/6 inhibitor. That is the idea of to block HR+ metastatic breast cancer, you could combine blocking the estrogen receptor, blocking the CDK4/6 pathway and blocking the PI3K pathway, which is like blocking three key drivers of the tumor growth and has already pioneered by the INAVO trial, which led to the approval of inavolisib.

Obviously, it is a way to block tumors for quite a long time. We have to see what is the future with these new agents. Chemistry is making progress and this is explaining the new agents that we are seeing coming to the clinics and coming in clinical trials.

We have made a long way since the very first agent and even also compared to alpelisib. So very happy to see the future development.

I think that we could conclude about these agents. We are at the very beginning, Nadia, of using both capivasertib and inavolisib in the routine clinics. It is something that will help us to understand and to manage the toxicity and finding the right patient to give them the best treatment option compared to chemotherapy and compared to other treatment options with endocrine therapy.

It is interesting also to keep in mind that, in the long-term, these agents blocking PIK3CA will play a greater role probably even in first-line and even it could be in the adjuvant setting. So we will have to wait to see that.

Dr. Harbeck: Yes, I could not agree more. These are very exciting times. I still remember those very early trials where we had side effects that were not manageable. We had a patient getting into a maniac phase and going on a shopping spree. We have come a long way from then now to inhibitors that can be managed quite well and where patients are not so bothered by the side effects for the majority.

I completely agree that we will probably see some very intriguing data also overcoming resistance and then maybe moving in selected populations, moving these drugs also in the early stage setting. It is very exciting. There is still data that we are waiting for. We are waiting for the CAPItello trial, the overall survival data. I mean, even if there is no advantage, these drugs are still very good in improving progression-free survival. I am still at awe of this median 2-year difference and median time to chemotherapy if you use inavolisib in those endocrine-resistant tumors in the triplet combination in the first-line. So exciting opportunities for our patients. It was a great discussion. Thank you so much.