Roche Holding AG (ROG.SW) Earnings Call Transcript & Summary

Good morning. Welcome to Roche Virtual Oncology SABCS Investor Event. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. [Operator Instructions] roche.com/invstors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours. Thanks, Henrik. And could I have the first slide, please?

So welcome to our eighth and last IR event for 2025, focusing on the Phase III lidERA results for giredestrant in early ER-positive breast cancer, which just got presented yesterday at the San Antonio Breast Cancer Symposium. As an upfront remark, let me just point out also the event originally had been scheduled for 60 minutes. We have now planned for 90 minutes just to make sure that we have enough time that we can take all your questions, which I'm sure there will be plenty of them. So let me quickly go through today's agenda. I will start today by providing a quick update on the big picture. I thought this might be needed considering the dense and impactful news flow we experienced in the fourth quarter. And following myself, the second speaker will be Maura Dickler, Vice President and our Global Head for Breast and Gynecologic Cancer Product Development. Maura will provide us an update on our expanding breast cancer portfolio, highlighting future development opportunities as we have several assets already in the clinic, which could become important combination partners in future development programs. Our second speaker for today, Aditya Bardia. Aditya is an MD, MPH. He is a fellow of the American Society of Clinical Oncology and the Professor of Medicine at the Geffen School of Medicine at UCLA. He was a principal investigator in the lidERA study and was a member of the Trial Steering Committee. Dr. Bardia will take us again through the Phase III lidERA results for in early ER-positive HER2-negative breast cancer in the adjuvant setting, which he also presented yesterday at the San Antonio Breast Cancer Symposium. Afterwards, we will start our Q&A session. In addition to our 2 speakers, we will be joined for the Q&A by Levi Garraway, our Executive Vice President and Global Head of Product Development and Chief Medical Officer; by Amr Elagroudy, our life cycle leader for hormone receptor positive breast cancer; Pablo Perez-Moreno, our Global Development Leader for giredesrant; and by Stefan Frings, our Deputy Chief Medical Officer. Could I have the next slide, please? Before we get started, I just wanted to quickly summarize the Q4 news flow and provide an update on the pipeline, some peak sales expectations and the overall outlook. As summarized on this slide, we had 3 major positive readouts in Q4, which when taken together have a significant impact on Roche's long-term investment case. So on the left side, you see the Phase III results for Gazyva in kidney disease. As you know, we just announced the U.S. and EU approvals for Gazyva in lupus nephritis. And in addition, in Q4, we communicated positive Phase III results in SLE, which comprises a significantly larger patient population. The SLE data are now planned to be presented at an upcoming conference. So it's probably SLEuro in March. And we also announced positive Phase III data in INS with data to be presented at the World Congress of Nephrology also in March of 2026. As you can see here, there is one additional Phase III study in membranous nephropathy to come in 2026. And let me point out here, taking all these studies together, the overall peak sales opportunity for Gazyva in kidney disease has now really increased to up to CHF 2 billion. Second, in the middle, you see the Phase III program for fenebrutinib in PPMS and RMS. In Q4, we announced a positive Phase III outcome for fenebrutinib in PPMS, which is the only study benchmarking a BTK versus a CD20 antibody. And in addition, we announced the first positive Phase III FENhance 2 in RMS. The second parallel study, FENhance 1 is to read out in the first half of '26. Overall, we believe fenebrutinib has now potential to become a best-in-disease medicine, and we have raised our peak sales expectations from CHF 2 billion to CHF 3 billion to more than CHF 3 billion. I can also confirm already that the PPMS data will be presented at ACTRIMS in February, whereas the RMS data will be presented at another conference once we have the FENhance data -- FENHNCE 1 data available. And just to confirm, RMS and PPMS data will be filed together in 2026. Finally, on the right side, you see the Phase III giredestrant development program, where we have reported now 2 positive Phase III studies, positive Phase III evERA results in the post-CDK4/6 setting, second-line plus ER-positive breast cancer, which were announced end of September and got presented already in October at ESMO. And in Q4, we now announced and presented positive Phase III lidERA results in the adjuvant setting, which we will discuss today in more detail. One additional comment here. U.S. filing for giredestrant based on the evERA data is now imminent, and we expect the initial launch for in the second-line setting to happen in 2026. Could I have the next slide, please? Let me also quickly provide an update on this slide, showing the 19 NMEs, which could launch by 2030. We have seen this slide before. The last time we showed it was at the Q3 results. What I want to highlight here is now we have 3 eventually even 4 NMEs, which are approaching near-term filing. These NMEs are vamikibart in UME boxed here in red, giredestrant in ER-positive breast cancer, which I mentioned already, the U.S. filing is imminent, and then potentially fenebrutinib in RMS and PPMS if the second RMS study reads out positive in first half '26. And finally, not shown on this slide, we are also looking into potentially filing setralizumab in that, but the filing decision has not yet been taken. Also to call out here on this slide, you can see that we have increased peak sales estimates for fenebrutinib from previously CHF 2 billion to CHF 3 billion to now more than CHF 3 billion. Next slide, please. This is another slide I quickly wanted to comment on. We had shown this slide last time at Pharma Day, providing a bit of a mid- to long-term outlook for the company. Two comments here from my side. This slide will need now to be updated, and we will do that in the first half of '26. We had previously communicated that our on-market portfolio, this is shown in light blue, is expected to deliver growth until '28 and thereafter to be flat, always fully compensating for expected 1 to 1.5 billion of annual generic erosion. As you can imagine now with the Q4 trial successes, this picture has now changed fundamentally with a clearly improved visibility on the long-term growth outlook. With somewhere between 2 to 4 NMEs now approaching filing and overall raised peak sales expectations, including the higher expectations for Gazyva and kidney disease, we expect now to deliver pharma growth until 2030 and beyond with the higher-value post bar portfolio only starting to read out from 2027 onwards. In 2027, we expect already the first major readouts from this portfolio with Afinkibart in IBD, pegozafermin in MASH and potentially trontinemab at year-end 2027. Can I have the next slide, please? Another Pharma Day slide, which you know well, where I would expect now some material changes to occur. As we had mentioned previously, consensus carried very little peak sales expectations for fenebrutinib and giredestrant, largely due to disappointing readouts from in-class competitor molecules. For giredestrant, we had pointed out that the CHF 900 million peak sales would more or less cover the peak sales expectations for evERA alone in second line plus. So that any additional success would be pure upside. And that's, of course -- this, of course, explains now, to some extent, the recent share price move, which we have seen. For fenebrutinib and MS there were only CHF 700 million peak sales in and also the opportunity for Gazyva in kidney disease seems not yet fully captured by the consensus. Next slide, please. This slide is just here to finish the 2025 news flow. There is one more positive Phase III trial, which we announced today, which also came in, in the fourth quarter. That's the PiaSKY in aHUS, the Phase III COMMUTE-a trial, which represents a smaller opportunity of up to CHF 0.5 billion, which is -- which has been positive. And if we go to the final slide, I just wanted to provide here an updated 2026 news flow slide. You see now a lot of U.S. EU filings scheduled for next year. And in terms of pivotal study readouts, we will have one additional giredestrant readout in first line. That's persevERA. The second first-line study in -- for giredestrant pionERA is to come a year later in 2027. And then also, you see here the one remaining study for Gazyva in membranous nephropathy. We also have additional line extensions reading out next year for Itovebi our PI3 kyanese inhibitor, which is developed in ER-positive and HER2-positive breast cancer as well as Lunsumio in follicular lymphoma and we have the first pivotal readouts for 2 new molecular entities for divarasib, our second-generation KRAS G12C inhibitor to be developed in non-small cell lung cancer and for sefaxersen our Factor B antisense oligonucleotide developed in IgAN. And with respect to the earlier pipeline, 2026 will be the year of our obesity CVRM portfolio with all NMEs having Phase II readouts. And with that, I will close my upfront remarks and hand over to Maura to run us through our emerging breast cancer franchise. Maura, please.

Yes. Thank you, Bruno. And next slide. And today, I'm excited to share our strategy for our breast cancer franchise at Roche. Breast cancer is 1 of the 4 end-to-end oncology disease areas where we will focus to accelerate innovation from discovery through launch and to expand our leadership to ER-positive breast cancer. We have rebuilt our breast cancer pipeline with clear focus on key priority pathways and are accelerating our time lines to best position the breast franchise for success. Next slide. We would like to share with you our current pipeline in solid tumor oncology. In breast cancer, we have one of the strongest portfolios. Giredestrant has become the focal point of this program as it has the potential to serve as a new endocrine therapy backbone in ER-positive breast cancer. We are also well positioned to develop combinations with our molecules to inhibit aberrant signaling pathways that drive breast cancer progression. Next slide. ER-positive HER2-negative breast cancer represents a significant market opportunity, accounting for about 70% of breast cancer. In addition, ER-positive HER2-positive disease constitutes another 9%, which represents more than 50% of the HER2 population. The majority of these patients are diagnosed with early-stage disease and therefore, adjuvant endocrine therapy constitutes the largest population of patients. There remains an unmet need for more effective and tolerable therapies with improved adherence to increase the chances of cure. Next slide. Presently, we are building upon Roche's pioneering work developing transformative therapies in HER2 and also focusing on other key signaling pathways that underlie breast tumor dependencies. We have a portfolio of potentially best-in-class differentiated molecules that are targeting the estrogen receptor with giredestrant, the PI3K pathway with Itovebi, the CDK pathway with GDC-4198 and the HER2 pathway with ZN-1041. Our goal is to redefine breast cancer. Next slide. Despite advances in treatment, a high unmet need remains in ER-positive breast cancer. Up to 1/3 of patients on adjuvant endocrine therapy eventually develop a recurrence. Existing endocrine therapies have incomplete suppression of the ER pathway and contribute to adverse events. While available and efficacious, CDK4/6 inhibitors cause significant side effects, including neutropenia, diarrhea and elevated liver enzymes, leading to discontinuations and are limited to certain patient population. In the first-line metastatic setting, more than half of patients experienced progression within 2 years on endocrine therapy and CDK4/6 inhibitors and many patients become resistant to subsequent endocrine therapies. Next slide. Giredestrant is a next-generation oral SERD and full ER antagonist designed to drive deep inhibition of ER signaling. Preclinical data demonstrates greater potency of giredestrant compared to other SERDs, and we are presenting supportive preclinical data at this conference. Giredestrant demonstrated superior antiproliferative activity with significant reduction in Ki67 and ER expression in both the coopERA and the EMPRESS trials. Ki67 reduction predicted outcomes of adjuvant endocrine therapy trials. Importantly, giredestrant was well tolerated with no dose-limiting toxicities. Next slide. In the evERA trial, giredestrant plus everolimus demonstrated a statistically significant and clinically meaningful improvement in progression-free survival in the ESR1 mutant and ITT populations after CDK4/6 inhibitors compared to the standard of care endocrine therapy plus everolimus. There was an overall survival trend favoring the giredestrant arm across these subgroups. The giredestrant plus everolimus doublet had a manageable safety profile, including no photopsia. We are presently sharing these results with health authorities. Next slide. We have initiated a broad clinical development plan for giredestrant across patient populations. Highlights of the CDP include the Phase III persevERA trial in a frontline endocrine therapy sensitive population anticipated in the first half of 2026, the Phase III pionERA trial in a frontline endocrine therapy resistant population with physician choice of CDK4/6 inhibitor and the Phase III heredERA trial in a hormone receptor positive HER2-positive frontline maintenance population in combination with Phesgo. In early breast cancer, giredestrant plus CDK4/6 combinations are being evaluated with an ABEMA safety substudy fully enrolled and a RVO substudy planned. And we will be sharing the lidERA data with you soon. Next slide. Shifting to Itovebi. Itovebi is an alpha-selective PI3K inhibitor that can be administered safely in combination, allowing additional synergistic inhibition of the estrogen receptor and CDK4/6 pathways at standard doses. Itovebi and INAVO120 has defined a new standard of care in frontline PIK3CA mutant endocrine-resistant breast cancer, demonstrating a statistically significant improvement in progression-free and overall survival. There was a median 2-year delay to subsequent chemotherapy, which is a meaningful outcome for patients. Discontinuation rates were low due to adverse events, confirming manageable tolerability. Itovebi is now approved in the United States, EU and China and additional launches are ongoing. Next slide. We have initiated a broad clinical development plan for Itovebi. Highlights include the Phase III INAVO123 study initiated in frontline endocrine-sensitive patients, the Phase III INAVO121 study, which is a head-to-head versus alpelisib and the INAVO122 studies in HER2 maintenance setting, the Phase II neoadjuvant study of Itovebi, ribociclib and letrozole, the neoTOV study and an additional adjuvant study is being considered. And we have also reported promising clinical activity of Itovebi in combination with giredestrant in an arm of the MORPHEUS study and a study of Itovebi and giredestrant and GDC-4198 is planned. Next slide. GDC-4198 is a potent inhibitor of CDK4 with substantial activity against CDK2 designed to address key resistance mechanisms that develop when targeting this pathway. Preclinical data demonstrates similar in vitro potency to parental and resistant cell line. GDC-4198 delivers similar activity as one molecule compared to atirmo and tagtociclib in combination. Next slide. Early clinical activity of GDC-4198 is promising as monotherapy in the post-CDK4/6 inhibitor setting with durable responses seen in heavily pretreated patients with manageable tolerability. Given this efficacy and tolerability, we have initiated a Phase Ib/II study of GDC-4198 in giredestrant in the post-CDK4/6 setting. So in summary, we have built a portfolio of exceptionally -- exceptional potentially best-in-class molecules. We have launched Itovebi, delivered positive data on giredestrant in both the metastatic and early breast cancer setting and continue to develop best-in-class combinations with the addition of 4198. It's really now my honor to introduce Dr. Aditya Bardia, maybe next slide, who's Professor of Medicine from UCLA, who will now present the giredestrant lidERA data. So Aditya?

Thank you so much, Maura. It's my pleasure to present the results of the Phase III clinical trial, giredestrant was the standard of care endocrine therapy as adjuvant treatment for patients with ER-positive HER2-negative early breast cancer. Next slide. So as mentioned previously, this was presented at SABCS yesterday. These are my disclosures. In terms of background, ER-positive breast cancer is the most common subtype of breast cancer. More than 70% of early breast cancers are ER-positive HER2-negative. And for ER-positive disease, endocrine therapy remains the mainstay of management, including early breast cancer. If you look at approvals of new endocrine therapy in early breast cancer, the last approvals came with the introduction of aromatase inhibitors in early 2000s from the ATAC and BIG 1-98 study, which showed that anastrozole, letrozole were superior to tamoxifen. The hazard ratio in those clinical trials was about 0.8. Next slide. More recently, we've seen CDK4/6 inhibitors in combination with endocrine therapy that have shown increased efficacy, but have also introduced associated toxicities. Moreover, many patients discontinued treatment early because of safety, tolerability, thereby increasing risk of recurrence. So clinically, there's an unmet need to have a therapy that's more effective and better tolerated in the adjuvant setting. Next slide. Giredestrant or GDC-9545 is a next-generation oral SERD. The drug is designed to bind to ER, induce a confirmational change in ER that leads to full antagonism as well as degradation. One point to note is that these oral SERDs like giredestrant can block both ligand-dependent as well as ligand-independent ER signaling. And this is an advantage over aromatase inhibitors, which only block ligand-dependent ER signaling. Next slide. In multiple cellular lines as well as cellular viability assays, giredestrant has been shown to be more potent than other oral SERDs including GDC-0810, it's also been shown to be more potent than fulvestrant as well as tamoxifen. In early breast cancer, giredestrant demonstrated superior antiproliferative activity in the neoadjuvant trial in the coopERA study versus anastrozole in the EMPRESS study versus tamoxifen. As was mentioned by Dr. Dickler previously, we know that suppression of Ki67 in the neoadjuvant setting is a strong surrogate marker for improvement in invasive disease-free survival. So based on these results, the mechanistic data, the preclinical data as well as the neoadjuvant data, lidERA was designed to test giredestrant versus standard of care endocrine therapy in the adjuvant setting, which is the biggest setting in terms of patient population in ER-positive breast cancer. Next slide. lidERA is a global randomized Phase III clinical trial that enrolled patients with ER-positive HER2-negative early breast cancer, patients with Stage 1 to Stage III disease, both premenopausal as well as postmenopausal. They were randomized to giredestrant versus standard of care endocrine therapy, which could be tamoxifen, anastrozole, letrozole, exemestane. The study was fundamentally designed to find what is the best endocrine therapy in early breast cancer. In this trial, patients who are premenopausal also received ovarian function suppression, and that becomes relevant as we talk about AEs related to this trial, patients received ovarian function suppression with giredestrant AIs. It was observed with tamoxifen, but majority of patients who received tamoxifen also received ovarian function suppression. Giredestrant is also being combined with abemaciclib in the adjuvant setting. That's the lidERA breast cancer substudy. Next slide. The primary endpoint of the trial was invasive disease-free survival, and this was performed in the intention to treat population was analyzed using the log rank test, and it was considered positive if the IDFS analysis was statistically significant with a 2-sided p-value of less than 0.02. The prespecified efficacy interim analysis occurred when 336 IDFS events were observed. And at this time, interim overall survival analysis also occurred based on the hierarchical statistical design. Assigned protocol therapy and follow-up will continue to final overall survival analysis. Next slide. In terms of patient flow, 4,170 patients were randomized 1:1 to giredestrant versus standard of care endocrine therapy. Majority of the patients, 84% of the patients received aromatase inhibitor in the standard of care endocrine therapy arm and 16% received tamoxifen. The median follow-up at the time of data cutoff was about 32 months. If we look at treatment discontinuation at the time of the data cutoff, 347 patients had discontinued giredestrant and 520 had discontinued standard of care endocrine therapy. Next slide. In terms of baseline demographics, they were well balanced between the 2 arms in terms of race, region, menopausal status, about 40% of patients in this trial were premenopausal. In terms of disease characteristics, about 50% of patients in the trial had Stage II disease, about 40% Stage III disease and about 10% Stage 1 disease. 70% of patients in the trial had high-risk disease and about 30% had medium-risk disease. Majority of the patients received prior chemotherapy. So overall, the baseline demographics as well as the baseline disease characteristics were well balanced. Next slide. So these are the primary results related to invasive disease-free survival. Giredestrant was associated with a statistically significant and clinically meaningful improvement in invasive disease-free survival. It reduced the risk of invasive recurrence or death by 30%. This is a hazard ratio of 0.70, and this was statistically significant with a p-value of 0.0014. If you look at the Kaplan-Meier curves, we see an early separation in favor of giredestrant and the separation is maintained over time. If we look at 3-year IDFS results, it was 92.4% with giredestrant versus 89.6% with standard of care endocrine therapy arm. So about a 3% absolute improvement in invasive disease-free survival at this time. Next slide. If we look at the results by type of endocrine therapy, again, giredestrant was superior as compared to aromatase inhibitor with a hazard ratio of 0.73 and tamoxifen with a hazard ratio of 0.53. Next slide. And if we look at other subgroups, again, we see that giredestrant was pretty much superior to standard of care endocrine therapy in all the subgroups by age, region, menopausal status, risk, prior chemotherapy. Next slide. And if we look at the results by stage, for patients with Stage II disease, giredestrant was superior to standard of care endocrine therapy with a hazard ratio of 0.58 and for patients with Stage III disease as well with a hazard ratio of 0.74. For patients with Stage I disease, the confidence interval crossed 1, but the number of events were few in this subgroup, which is consistent with the natural history of Stage I disease. Next slide. In terms of distant recurrence-free survival, again, giredestrant was superior with a hazard ratio of 0.69. So this corresponds to a 31% reduction in the risk of developing metastatic disease was reduced with giredestrant as compared to standard of care endocrine therapy. And again, you see the curves here separate early and the separation is maintained over time in favor of giredestrant. Next slide. In terms of interim overall survival, the overall survival results are immature at this time, but a clear positive trend was observed in favor of giredestrant with a hazard ratio of 0.79. Overall survival testing will continue at future analysis. Next slide. And finally, in terms of safety, Overall, the incidence of AEs and serious AEs were comparable between the treatment arms. If we look at the mean dose intensity, that was close to 99% in both the arms. If we look at AEs with fatal outcomes that was lower with giredestrant, there were 6 deaths with giredestrant in the giredestrant arm as compared to 16 in the standard of care endocrine therapy arm. Similarly, if you look at AEs leading to treatment discontinuation that was lower in the giredestrant arm as compared to the standard of care endocrine therapy arm. So fewer patients in the giredestrant arm discontinued because of AEs as compared to the standard of care endocrine therapy arm. In terms of the percentage, it was 5.3% discontinuation in the giredestrant arm versus 8.2% in the standard of care endocrine therapy arm. Next slide. if we look at the type of AEs, this volcano plot summarizes the specific AEs. Arthralgias were the most common AEs seen in both the arms. As a reminder, in this trial, patients received ovarian suppression in addition to the endocrine therapy for patients who were premenopausal. The other AEs that were seen include menopausal symptoms. While the rate of musculoskeletal symptoms were similar between giredestrant and standard of care endocrine therapy, discontinuation because of AEs were lower in the giredestrant arm as compared to standard of care endocrine therapy arm. So if we look at musculoskeletal disorders, the rate of discontinuation was 4.4% in the standard of care endocrine therapy arm. And in the giredestrant arm, it was lower 1.8%. In terms of AEs that were higher with giredestrant, that included bradycardia. Majority were Grade 1. As a reminder, Grade 1 bradycardia is asymptomatic. It does not need any treatment old or discontinuation and no medical intervention is needed for Grade 1 or asymptomatic bradycardia. This is something that's picked up on routine monitoring. There were no Grade 3 or Grade 4 events in terms of bradycardia seen in both the arms. And then finally, venous thromboembolic events that was lower in the giredestrant arm, Grade 3, Grade 4 as compared to the standard of care endocrine therapy arm, which also included tamoxifen that can induce venous thromboembolic events. Next slide. So in summary, since the approval of AIs in 2000s up to almost 25 years, lidERA is the first study in the adjuvant setting to demonstrate benefit with a novel endocrine agent in early breast cancer. Next slide. With a median follow-up of 32 months, lidERA demonstrated a statistically significant and clinically meaningful improvement with upfront giredestrant versus standard of care endocrine therapy in ER-positive, HER2-negative Stage I to III early breast cancer. The invasive disease-free survival hazard ratio was 0.70. The 3-year invasive disease-free rate was 92.4% versus 89.6%. So that's about 3% absolute improvement in IDFS. Overall survival also trended in favor of giredestrant and distant recurrence-free interval was improved with giredestrant versus standard of care endocrine therapy with a 31% reduction in the risk of developing metastatic disease. Next slide. And in terms of safety, that was favorable and consistent with the known safety profile of giredestrant, the discontinuation rate was numerically lower with giredestrant as compared to standard of care endocrine therapy, and that's an important observation in the adjuvant setting. So overall, the results support giredestrant as a potential new standard for patients with hormone receptor positive HER2-negative early breast cancer. I'd like to thank and acknowledge patients, families, the Global Steering Committee, TRIO NSABP Foundation as well as all the investigators who were involved in this trial. Thank you so much.

Excellent. Thank you. So with that, we will open the Q&A session. The first questions go to Emmanuel Papadakis from Deutsche Bank.

Hopefully you're hearing me okay. Maybe I'll take 2, if I may. Congratulations on the data. Perhaps a question around subgroups and a question on potential labeling and guideline implications. So the question on subgroups is just we didn't get any disclosure of benefit by nodal subgroups, which is something we've seen in prior studies in the settings such as NAT. So could you just confirm that the benefit in terms of hazard ratio was consistent in the node negatives, which was around 1/5 of the population in the study with those with a nodal count of 1 or 2 to 3? That would be very helpful. And then just in terms of labeling and guideline implications, perhaps you could give us a sense, it was a relatively high-risk population enrolled in the study to give us a sense of what you're anticipating the FDA label may look like? Are you anticipating a high-risk wording in Stage II and III patients or something akin to the Kisqali wording for adjuvant breast cancer or something close to Verzenio, which is indicated for node-positive, high-risk patients, for example? And then any thoughts you could share on NCN guideline implications as well would be helpful.

Who wants to take the first question maybe on the subgroups.

I can take that. I'm Pablo Perez Moreno, I'm the Global Development Leader for giredestrant. So when we look at the subgroups, as we shared in the presentation, the subgroups are generally consistent, and this includes novel status.

The stage was reflective of the status.

Exactly. Well, Stage II includes patients with N1 -- mainly N1 disease. And as you highlighted, Stage II, although includes some patients with no negative disease, it's also reflective of the activity in nonnegative patients.

Okay. Then who is taking the second question, which is a bit more looking already further ahead in terms of labeling, how this could look like?

Maybe I'll jump in on that. Obviously, it's difficult at this stage. Actually, we generally don't comment on labeling before there is a label, but I would just underscore the point that Pablo made, which is that we -- there's consistency of the data across all of the subgroups that we looked at. We're one of the few adjuvant studies to include Stage I. And so -- but even there, directionally, things are consistent. And certainly, as was mentioned, across Stage II and III. So the consistency of the data, we think we'll speak prominently here, but we can't discuss specifics of label at this point.

Maybe on NCCN guidelines.

Yes, absolutely. In terms of NCCN guidelines, the study met its primary endpoint and IDFS was analyzed in the intention to treat population. So we would expect in terms of guidelines that the drug will be used in Stage I to Stage III because that was the primary endpoint. And so in terms of guidelines, this would be in the upfront setting, in the adjuvant setting as an option for patients with Stage I to III ER-positive breast cancer.

Emmanuel, did this answer your question?

Yes, that's very helpful. And I'll circle back in the queue if there's time there.

So our next questions go to Colin White from UBS.

Colin White from UBS here. It's a follow-on, I guess, to Emmanuel's question there was we've been getting a lot of questions given that CDK4/6 inhibitors are used in a medium to high-risk population, just how broadly giredestrant will be used. I was wondering if Dr. Bardia could comment how much it would be used in the lower-risk patients from the lidERA criteria, assuming it has a label, how much you think it might be used in even lower-risk patients, that 55% of patients you identified as lower risk and also the potential for use after a CDK4/6 inhibitor. Yes, that's my first question. And then my second question is a little bit about the difference between lidERA study and other adjuvant studies, which are -- which we're expecting, where patients in lidERA had only had less than 12 weeks of endocrine therapy, whereas for some other studies like CAMBRIA-1 or EMBER-4 for other oral SERDs, they've had about 2 years of prior endocrine therapy. So just comments on how we'll be able to maybe assess that data. And if it's an advantage that Roche has shown a benefit in patients that have had such little previous endocrine therapy. That's my question.

Great question about CDK4/6 inhibitors. So I would break this down by stage. lidERA included patients with Stage 1 disease. Those patients were not included in NATALEE or MonarchE. So if the drug is approved for patients with Stage I disease, this would be the only endocrine therapy option without a CDK4/6 inhibitor. In patients with Stage II disease, that was also included in NATALEE, so there is some patient overlap. And ultimately, it will be a discussion between the patient and the provider, talking about the efficacy, which looks very favorable. If you do cross-trial comparisons with its caveats, the hazard ratio in NATALEE was about 0.75. In lidERA, it was 0.70. These are cross-trial comparisons. And we would also talk about toxicity, when we talk to a patient about a drug, so both efficacy as well as toxicity with CDK4/6 inhibitors such as ribociclib, common toxicities that are seen include increase in liver enzymes, QTC prolongation as well as myelosuppression. So that will be a discussion in terms of the AE profile. And then in patients with Stage III disease, there was overlap with MonarchE. And again, it will be a discussion between the patient and the provider talking about the efficacy as well as the toxicity of these drugs with abemaciclib common toxicities, including diarrhea, myelosuppression. So based on the efficacy and the toxicity profile, these drugs would be used. Overall, it appears that as a single agent, which is not surprising, the drug has lower toxicity as compared to combination therapy. So for the appropriate patient, giredestrant would be a good option to consider?

Second question?

Yes, I can start addressing the second question. Thanks for that question on comparing with some of the other designs. So lidERA, as we disclosed, it's addressed -- or fundamentally addressing the question of what's the best endocrine therapy upfront. And clearly, the results show that giradesant is superior to AI or tamoxifen, which are the current standard of care. When we think about the other study designs, they allow 2 or 3 years of endocrine therapies, which although we haven't seen the results, we're significantly ahead in this field. We anticipate that, that is an option that may become available in the future. However, in thinking about how the landscape might shape, we believe that an upfront choice of a better endocrine therapy, it's a better option for patients.

And I believe the 12 weeks, which you mentioned, were just the feasibility to include patients who had already started, but they could then enroll the trial.

Exactly. That's a common design. And sometimes patients as they are finishing their chemotherapy, they go through radiation therapy are started on endocrine therapies. So it's really not designed to have the switch concept. Many, many patients have a few weeks of endocrine therapies while they're finishing some of their treatments and then they're allowed in the study. And there were not a lot of patients. I mean, that is information we haven't disclosed and we haven't fully analyzed, but the majority of patients have not received any endocrine therapy prior to the beginning of the data.

Maybe I'll just add one more point on this. Obviously, it will be a long time before there's any kind of comparison between doing a switch approach versus starting upfront with a particular endocrine therapy. However, in oncology, a guiding principle, especially with targeted therapies is that you usually want to lead with your best option. It's not common in oncology that you would sit on the best medicine and wait until later. In general, you want to lead with your best options, especially if you have a chance to cure people and especially if the safety -- if the tolerability profile is favorable. So obviously, we can't speak about any data here because it will be a long, long time before we compare, but that is a general guiding principle. And as Pablo pointed out, we have shown that giredestrant is superior to alternative endocrine therapies in the adjuvant setting.

And maybe last point on the early separation of the iDFS curve. So we see already the effect of giredestrant kicking in at 6 months on iDFS. But then consider in [ CAMbre-1 ], when you only start after 2 years of endocrine therapy, this benefit is already lost for patients. You have already patients relapsing. So very clean design lidERA, very clear answer, and it's superior and in line with what CDK4/6 inhibitors are showing as well.

Colin, did this answer your questions or you have a follow-up question?

Yes. No, that's great.

Very good. Next question is go to Peter Verdult from BNP Paribas.

Pete Verdult here from BNP. Just 2 maybe for Dr. Badia, just a variation on theme. I don't think you'll be surprised. But just interested to explore a little bit more how you think the standard of care in adjuvant breast cancer will change in light of lidERA. I mean when you speak to people like Fabrice Andre, therefore CEO of [indiscernible] they're convinced SERD are going to be treatment practice changing. The discussion yesterday, perhaps a little bit more reserved in the absence of sort of SERD combo data with CDK4/6. So interested in your view, Dr. Badia, were giredestrant hypothetically approved tomorrow, how widely you'd be using it in your treatment practice? And then just a question on crystal ball gazing. When the appropriate studies are done, would you predict that, that SERD will show utility in that low-risk adjuvant patient group going forward?

Yes, absolutely. In terms of use of giredestrant when it is approved, it's the best endocrine agent we have at this time. So it would essentially replace AIs. Instead of AIs or tamoxifen, I would preferentially use giredestrant as we were discussing previously, Stage 1, Stage 2 disease, even in patients with Stage III disease. In patients with high, high-risk disease, whether giredestrant as a single agent is used, whether AI plus CDK4/6 inhibitors are used or giredestrant in combination with the CDK4/6 inhibitor is used. I think that's an open question at this time. Many physicians once there is safety data available with giredestrant plus, say, abemaciclib, we will feel comfortable using that in patients with high, high-risk disease because at the end of the day, we want to use the best endocrine option. The best endocrine option at this time appears to be giredestrant over AIs. So essentially, that's what would be used.

And utility in the -- eventually in the low-risk group, do you see that being an option or potential?

Absolutely, absolutely. So essentially, that's why lidERA was fundamentally designed to test the question what's the best endocrine therapy option. And we see that giredestrant is superior to AIs and tamoxifen. So wherever AIs and tamoxifen is being used, that will get replaced with giredestrant in early breast cancer.

Questions from your side? Then we move on. Next in the row would be Richard Vosser, JP Morgan.

A couple of questions from my side. Just on that idea of having enough safety data in combination with the CDK4/6, when could we get the abemaciclib substudy? And second question is, does Roche plan to do a combination study anyway in the adjuvant setting for giredestrant? And would that sub-study be enough to tip the hand maybe probably not approvable for a combination, but what's the thoughts there? And then secondly, just maybe for Dr. Badia and maybe also for Roche. We've seen in the subgroup versus AI obviously, a strong benefit here in the adjuvant. What's the thought process now around first-line treatment in wild-type patients as we look ahead to maybe persevERA? Thoughts of the read from lidERA, would be useful to hear your thoughts?

Thank you. I'm going to start with the first question. The verimaciclib sub-study is fully recruited. We anticipate data potentially towards the end of next year. We're looking into how that data matures. For other combinations, we are opening a similar approach potentially with more patients on ibociclib with the same concept as a sub-study on lidERA. And I think there was a second question on how do we anticipate -- the -- was it on the label or the use, but I can comment. As Dr. Badia said, depending on access and physicians' willingness to combine, that could be an option that could become available. I don't know, if anyone else wants to comment on this.

Maybe I could just jump in about sort of other additional studies that are planned. We're really considering our options now and are not able to publicly discuss that presently, but are definitely exploring multiple options to consider.

Maybe I'll jump in on the read-through or not to persevERA. I mean one thing that's clear is that giredestrant when breast cancers are dependent on the estrogen receptor for viability, giredestrant can perform extremely well. We've now seen that in the metastatic setting where the second-line metastatic setting, where ESR1 mutations essentially mark the tumors that still dependent on the estrogen receptor. It performed very well there. And now we've seen it in the adjuvant setting. All of those patients are, by definition, dependent on ER signaling. It has worked very well there. So clearly, in the front line, the likelihood that it's successful certainly hasn't gone down with these results. However, we do need to caveat it. This is now data in combination with the CDK inhibitor. So we -- certainly, the chances are reasonable, but we have to be cautious because it's a different context, a different treatment combination. So we just have to see how the data plays out. But certainly, the overall scientific hypothesis remains very strong for the persevERA study.

Any additional questions, Richard?

No, that's fine. Thank you...

And we move on. Next questions come from Luisa Hector from Berenberg.

In terms of lidERA, do you think that regulators and doctors will want to see some longer-term efficacy data for approval or for adoption? And specifically in the Stage 1 subgroup, and this is clearly an open space in terms of treatment, but is there enough data from the subgroup of Stage 1? You flagged low level of events just due to the nature of the Stage 1, but do we have enough data there? So that's the first question. I'd love to hear from Dr. Badia on that. And then I wanted to check in terms of recruitment into lidERA, was everything broadly as you planned it, sort of Stage 1 comparator arms? And then check on the U.S. subgroup because you showed 40% or so in U.S. and Western Europe. Can you just confirm you have enough U.S. patients as well within that recruitment criteria?

Yes. In terms of use based on the data, I would say, yes, and we have historical precedents. If you look at the MonarchE results or the NATALEE results, they were presented with a median follow-up that's very similar, and we had 3-year iDFS results, and that led to the uptake of these agents. So we have precedents that as long as the curves separate and we're seeing good separation of the curves, we know that over time, this will be maintained. This drug also has lower toxicity as compared to standard of care endocrine therapy. So once it's approved, I think there will be a lot of enthusiasm in terms of using this drug, not only from an efficacy perspective, but also a tolerability perspective, which is critical in the adjuvant setting. And that's why I feel even for patients with Stage 1 disease, we would be enthusiastic about using this drug because of the [ aduleant ] safety profile.

Yes. And for regulatory authorities, it's about benefit risk. Keep in mind, when MonarchE and NATALEE trials reported, they added a lot of tox in comparison, certainly what we see here with lidERA, where we have even some benefits on toxicity. So from a benefit risk perspective, iDFS is an approvable endpoint. Over survival is showing clearly pointing in the right direction. There should be no impediment what we currently see from authorities, which would put a show stop in front of us.

And I think there was another question on U.S. recruitment. And to follow up on this, of course, we're going to continue to follow up on the study. We expect the results to remain consistent, and we're going to continue reporting as the data matures. U.S. recruitment was close to 10% in this study. So we believe that's a significant representation from the U.S. And as we disclosed, if we consider U.S. or North America plus Western Europe is about 40%.

Lisa, any additional questions or -- the next questions go to James Quigley from Goldman Sachs.

I hope you can hear me. So 2 questions from -- or 2.5 questions from me. So just following up, Levi, on the probability of success for persevERA and your comment on the endocrine sensitivity. So you had that predictive transcriptomic analysis that seemed to work pretty well for the adjuvant setting. But what does it look like in terms of the first-line setting endocrine sensitivity relative to adjuvant? And did you enrich persevERA for those patients who were more highly endocrine sensitivity? And what was the cutoff to assess that? Second of all, just double-clicking on the combination plan in the adjuvant setting. Obviously, you've got the sub study with Verzenio. You've just mentioned that the Kisqali substudy will be larger. But what do you need to show here? What evidence do you need in order to particularly gain reimbursement here? And what level of evidence would you need to gain reimbursement support for the combination? And similarly, on that level, does it necessarily matter? Or would it be a case of giredestrant plus GDC-4198 could be your combination strategy? Also would love to know if that could be combined into a single pill. And the half question, what are the filing plans in the U.S. and globally for the adjuvant setting?

So I'll start on the persevERA. So to the first of transmission, we didn't enrich for endocrine sensitivity per se in the front line. We -- because certainly in the frontline setting, in the treatment-naive setting, you don't really -- there's no mechanism to enrich for endocrine sensitivity. What we did do, however, is there is some enrichment for patients who had progressed relatively soon after receiving adjuvant therapy because there was some evidence that given what we know about fulvestrant, for example, in kind of analogous settings and given the bioavailability of giredestrant and its obviously ability to function as a potent SERD, we felt like that might -- there might be some advantage in such patient population. So we will need to see whether or not that hypothesis plays out. But certainly, there was no priority way to enrich for sensitivity to endocrine therapy. So maybe I'll see if others want to take the follow-up questions.

The question on there was a question... Is required in order to obtain access in combo with CDK4...

Sorry, I'm happy to take the question about the expectation for access. I mean, usually, the -- for guidelines, the efficacy endpoint is preferred. So we expect the -- both the sub lidERA studies for both lidERA and Kisqali to provide important safety information to encourage physicians who would like to use both agents together. But it's difficult to speculate at this time that this would lead to label or guidelines change.

James, I think you had a couple of additional questions.

And definitely, we're like having plans to combine giredestrant with the 4198. CDK, but we're also considering other plans to combine giredestrant with other CDKIs other than the 4198. And this is actively being discussed now, and it's too early to disclose any of that.

Yes. And maybe I can just build on that. And obviously, combining giredestrant with other molecules in our portfolio is really core to our strategy, including 4198. And as Amar said, we've initiated a Phase I/II study of giredestrant and 4198 in the second-line metastatic setting. But it's really too early now to speculate on the combinations of these 2 molecules.

James, any additional questions?

The only additional one was the filing strategy or time lines for the adjuvant setting.

Yes. Yes.

Yes. So we are planning to file for both the U.S. and Europe next year.

Okay. Then we go on. Next questions go to Sachin Jain from Bank of America.

I've got a few more on positioning, if I may. So firstly, back to Dr. Badia, just an answer to prior question, I think it was Pete's question on replacing endocrine therapy. Was that in reference to where it's used as mono? Or does that include where it's used as combo with CDK4/6? Obviously, one of the key debates in the market overnight has been the monotherapy endocrine usage is limited in that medium high risk given CDK4/6 usage. And the second is if you could just comment to what percentage of the population you think is unique to lidERA. So you've commented that Stage 1 is, but I wonder if you could overlap that. But I think it's your Slide 20, which points to intermediate high risk being 50% of the population. Just trying to get a sense of what percentage of intermediate high risk you see as Stage 1 that is unique to lidERA? And then the third question follows on, on the combination sort of topic. You talked to Kisqali, Verzenio sub-study, but I wonder whether persevERA, which is the first data of the combination could actually support combination usage in the adjuvant setting. And apologies for the background noise.

Great. 3 questions. So I'll start first in terms of use of endocrine therapy as monotherapy for patients with medium or high risk. At the end of the day, we want to use an agent that is most efficacious and has lowest toxicity. That's the guiding principle in terms of treating patients with cancer, including breast cancer. Endocrine therapy plus CDK4/6 inhibitors showed that they were superior to endocrine therapy as a single agent, but that was with aromatase inhibitors and the hazard ratio was 0.75, and that led to uptake of CDK4/6 inhibitors for, I would say, a number of patients with Stage III disease, but it was less for patients with Stage II disease given the toxicities that we also see with CDK4/6 inhibitors. Even in the clinical trial, the rate of discontinuation of CDK4/6 inhibitors in NATALEE, MonarchE was between 15% to 20%, while in lidERA, this was less than 5%. So it just tells you more about the tolerability of the drug in this setting. Now with lidERA, you see giredestrant in patients with medium as well as high-risk disease showed an improvement in invasive disease-free survival with a hazard ratio of 0.70. Again, cross-trial comparisons, but it looks favorable as compared to endocrine therapy plus a CDK4/6 inhibitor. So many physicians, particularly for patients with Stage II disease or patients with Stage III disease who have, say, 1 positive node will consider giredestrant as a single agent to balance the efficacy with the toxicity profile. But in patients who have, say, 10 positive nodes, many would be concerned about using just single agent would want to combine that with a CDK4/6 inhibitor, such as abemaciclib that's shown improvement in this setting. And that's why the safety data would be very helpful. Once there is safety data with giredestrant plus abema, -- for patients with high, high-risk disease, many oncologists will discuss with the patient, but we feel comfortable describing giredestrant plus abema because at the end of the day, again, we want to use an agent that gives the best chance of cure in the adjuvant setting.

I think there was this follow-on question from Sachin as well, whether the first-line data, the combo data would help in establishing safety data for combos, if I got your question right, Sachin?

Yes, that's spot on. So that data obviously persevERA comes a long time before the Verzenio and Kisqali substudies.

It's tough to speculate without seeing the results. If the results are positive, there will be further confirmation that the best endocrine agent in combination with the CDK4/6 inhibitor is superior to AI plus CDK4/6 inhibitor. But on the other hand, as well, if the results are less significant or even if this is a negative study, that would not necessarily dissuade me from using the drug in the adjuvant setting. Metastatic setting is a different setting. It includes patients, who have endocrine-sensitive disease, some resistant as well. It's looking at combination therapy. So it can maybe influence some adjuvant use. But I think ultimately, in the adjuvant setting, we have lidERA study. It's the combination of giredestrant plus abema that will further guide the use of combination therapy.

And then I think we had one question remaining, which was about the percentage difference in terms of the patients included when you compare lidERA versus NATALEE.

So I was just trying to get a sense of the medium high risk, what percentage is Stage 1 that is unique to lidERA?

So all patients with Stage 1 are unique to lidERA because that was not included in NATALEE or MonarchE. So any patient who had Stage 1 disease, that's only the lidERA population. Overall, that was about 10% in this trial. Patients who had Stage 2 disease, that's where it overlaps with NATALEE. And then patients with Stage III disease, not all, but the high-risk ones that overlaps with MonarchE.

Apologies. Maybe my question. I'm just trying to understand what percentage of medium high risk in the population not in the study with Stage 1. So in your slide, Bruno, you have sort of 50% of patients being medium and high risk. What percentage of that 50% is Stage 1 is therefore unique to you?

So patients who have Stage 1 disease, that would be included in the medium risk that would not be included in the high-risk population. So if you look at the medium risk, that was about 30% in this clinical trial. And so that predominantly is patients with Stage 2 and Stage 1 disease. And Stage 2 was about 50%, Stage 1 was 10%. So if you do the calculations, you can probably see that maybe 20%, 25% of patients in the medium risk disease and Stage 1 disease.

Does this help, Sachin?

Yes, I'll leave it at that.

Okay. All questions from your side. And next one would be Simon Baker from Redburn.

2, if I may, please. I just wonder if we could dig down into the dose interruption, AEs leading to dose interruptions, about twice as high in the giredestrant arm. I just wonder, are there any -- what was the nature of those -- the AEs leading to those dose interruptions, the length of dose interruptions? Did it have any outcome on -- any impact on outcomes? And does it give rise to any prospective dosing adjustments that you can take going forward? And then secondly, a question for Dr. Badia, and it's kind of asking in reverse a question that's been asked a dozen times before on this call. Given the consistency and the magnitude of the benefit we've seen here. Are there any patients within this population where you would not use giredestrant?

So I'll take the first question. Dose intensity was high in both arms, including the giredestrant arm. And as we highlighted dose discontinuations were lower, but you're asking about dose interruptions. The data started in 2021. What we knew about the safety profile of the molecule at that time was different from what we know today in 2025. There was some protocol mandated schedule of assessments and some physicians had to interrupt because of, let's say, findings that patients were interrupted for a short period of time. As we looked into dose intensity, those interruptions didn't impact dose intensity. And then what's probably considered a harder endpoint, which also physicians consider either toxicity or patients having AEs where the dose discontinuations, which were low with giredestrant.

Yes. And in terms of the second question, is there a patient population where I would not consider giredestrant? Based on the trial, I don't think so. If you look at the subgroups, the benefit was consistent. If you look at AEs, bradycardia was predominantly Grade 1. If a patient has Grade 3, Grade 4 bradycardia, maybe that's a setting where we would hold giredestrant if it's Grade 4 discontinue, but that was not seen in this clinical trial. So at least based on the data we have, I don't see a patient population or patient scenario where I would not use giredestrant.

Next questions go to Paul Koh from Cowen.

This is Steve Scala from TD Cowen. I have several questions. I think you said 10% of lidERA patients were from the U.S. Does that meet the expectation of FDA for U.S. approval? It would appear that it might not. Secondly, what does Roche's $3 billion plus peak sales guidance for giredestrant assume for competition from other SERDs in the adjuvant and metastatic settings. All things considered, the number seems quite low. So does that imply that Roche expects a high level of competition? I appreciate the number has a plus after it, but you could have said $4 billion plus or $5 billion plus $2 billion. And then lastly, has Roche performed the interim PFS analysis yet for perservERA? And is the interim or final PFS analysis coming in early 2026?

Let me maybe, Steve, just take the question on the peak sales. I think this is just a methodological setup here. We only provide when we guide 4 buckets, which is 1 to 2 -- what was it 0.5 to 1, 1 to 2, 2 to 3 plus. So 3 plus basically can mean a lot. It can be 3, 4, 5, 6, 7, 8, 9, 10, whatever you consider appropriate. So we do not provide more precise peak sales guidance like other companies do. We would not call out 6, 7, 8 or what we think is the right number.

And if I may add to that, Bruno, I think based on how advanced our readout is versus competition. So the next adjuvant trial is expected to read 2 years from now. And we believe with the efficacy and with the safety profile of giredestrant that we will be established as the best-in-class in that space.

On the U.S. enrollment, there's not a percentage cutoff that the FDA mandates for U.S. enrollment. What they want to see is that the results and the patient population are consistent with what one would encounter in the U.S. And so obviously, with a 4,000-patient study, we have hundreds of patients from the U.S. The effect in the U.S. was directionally similar to what was seen overall. And when you roll in similar populations such as Canada and Western Europe, you have even a much higher percentage of patients from the trial and the results are consistent. So we don't anticipate a challenge around the U.S. enrollment and applicability.

I would just add that the treatment is, I mean, basically identical across the world. It's Atomoxetine, AI a single-agent endocrine treatment. And certainly, there's no different health care context than to be applied. We are fully in line with what U.S. physician would expect to see.

Stephen, did this help? Or do you have follow-on questions on the competitive landscape?

The persevERA question is, have you performed the interim PFS analysis of persevERA? And what exactly is coming early next year? Is it interim or final?

So I can comment on that. What we have in 2026 is the primary analysis.

Okay. Did you say final analysis?

Yes, final. Yes, that's right.

Okay. Then we continue. Next questions go to [ Graham ] Perry from Citi.

Great. So just going back to the substudies on lidERA, the Verzenio and Kisqali ones. Could you just remind us what you said on Verzenio when we see the Verzenio one? And then if you're just starting the Kisqali one, just any sort of time line on data from that. Can you confirm that second one has got both intermediate and high-risk patients in it? And then do you think those combo studies could be enough to help reimbursement if, for example, they can get a compendia listing, for example? And then the second question is just how do you think about pricing analogs here. For aromatase inhibitors became generic quite a long time ago, they were substantially lower priced than oncology products today. And perhaps the closest comparator you'd have now would be CDK4/6, but perhaps just help us to think about how you're thinking about that at this stage.

So I'll start with the question on specific designs and time lines on the combinations with abemaciclib and ribociclib. As I mentioned before, the abemaciclib is fully recruited. We are following up these patients. We anticipate data towards the end of 2026. Ribociclib, we're starting now. What we have used with the abemaciclib study, it's used the inclusion criteria for abemaciclib mirroring MonarchE. So what we're going to do with ribociclib is mirroring the inclusion criteria of NATALEE.

And with regard to access, I might I like to think about this in 2 buckets. I think when it comes to ex-U.S., I don't expect like those substudies with safety endpoints will support reimbursement. But in the U.S., it could be a different story. And I think with additional data generation that we are planning to use, it's going to be a discussion within the health care system, if those data could support reimbursement.

Go ahead. Any additional questions?

Yes, just the pricing analogs one.

Pricing analogs, yes, CDK4/6 is this a reasonable pricing analog? Normally, we say too early. So we only will announce the price once we get approval. I think we'll leave it with that. Okay. Any additional questions?

No, that's great for me.

Okay. Then I think we will close the loop, and we have the final questions going to Emmanuel Papadakis. Emmanuel, please. Second set of questions.

I'll try and be quick. It was just a follow-up perhaps for Dr. Badia on your optimism on potential use as a monotherapy in the lower-risk population. Just trying to understand that a little better, since you had 0 patients classified technically as low risk in the study. As you mentioned, it was less than 15% Stage 1. In those, you had a 0.89 hazard ratio on iDFS. So just wanted to understand your optimism around potential clinical adoption in the lower to intermediate risk setting. Is that because you're expecting the regulatory agency may ultimately endorse a label explicitly encompassing a Stage 1 population? Is it because you're thinking oncology guidelines would recommend use in those patients? Or is it just that you think physicians will be so keen to upgrade their endocrine therapy for patients, they'll do that regardless of either of those 2 things? And then maybe just a follow-on on pricing. We have had some benchmarks established within the SERD space by the recent approval in LO and of course, as SERD do. There's been times in the past where Roche has been very willing to come in later and take a more egalitarian approach to pricing to open up access for a broader population. Is that something you would consider in this circumstance? It would seem presumably likely to access a broader population in the adjuvant setting, you might need to consider that.

So I can answer the question about patients with low risk or Stage 1 disease. The optimism is because we feel that this is the best endocrine agent based on the mechanistic preclinical as well as the clinical data that we've seen. And then also, this is the agent that has a better tolerability profile in terms of discontinuation as compared to AIs. And if we look at the hazard ratio, it's trended in favor of giredestrant. It's just that the number of events are few. So we need more follow-up before we would have a statistically significant result because that Stage 1 disease, the number of events are few. But because this is an agent that we feel is the best endocrine agent and also has a safety profile that is very clean, that is the reason why we're optimistic about this agent even for patients with Stage 1 disease. In terms of when we would see the results, I think at this time, further follow-up is continuing.

I think there was another question about pricing. And if I understood the question correctly, please correct me if I'm wrong, that whether we would consider like changing or adjusting the price based on the future patient population that would be approved through the address studies. If that's the case, I would say, I think we're in a good situation that we have both Avera and lidERA positive that will inform our pricing assumptions given that lidERA is going to be the broadest patient population. So I wouldn't expect future changes to the price based on subsequent study readouts.

Yes. Okay. One more question coming in from Richard Vosser, JPMorgan.

Just one follow-up to Emmanuel's question. Just in that low-risk population, the proportion of patients on tamoxifen, was it different? Did you have more tamoxifen use in the very low-risk Stage 1 patients compared to letrozole or something else? Or is it similar across the whole trial? Obviously, it might have implications for the efficacy advantage in those patients.

Thank you for the question. That's an excellent question. We -- we unblinded the study 3 weeks ago, and we still don't have that answer. However, very much with your thinking, we anticipate that the use of tamoxifen is leaning towards patients who are either premenopausal or lower risk, but acknowledging that we don't have that data yet.

Very good. And there is one more question from Cowen from Stephen Scala...

And apologies, another question about PersevERA. So there was a planned interim analysis that was to be performed when 70% of progression-free survival events occurred. And you answered the question earlier citing the final analysis. So should we assume that the interim analysis has passed and the study is continuing to final?

We don't comment on interim analysis. So at this juncture, we'll comment at the final.

Thanks for understanding, Stephen, but we cannot provide more granularity on that one. Okay. With that, I think we are at the end of today's call. I would like to thank all the participants here. I would like to thank the IR team members, who prepared the slide deck, that's [ Rafael Pavlolowski ] and Bruno Eschli and also Melanie Wolf for the event organization. I hope the event was helpful providing a timely update to our breast cancer franchise. If there are any remaining questions in the coming days or next week, please reach out to the Roche IR team. We are happy to further follow up. And with that, I would like to wish you all, in case we have no interactions anymore, I would like to wish you a peaceful holiday season, Merry Christmas and a good start into 2026. Bye-bye.