Ovarian Cancer — Ursula Matulonis, MD

DR MATULONIS: Hi, I'm Ursula Matulonis and I'm from the Dana-Farber Cancer Institute in Boston, Massachusetts, and a real pleasure to be here for the Year in Review for Research To Practice. It's always a pleasure being part of these programs.

So I am going to focus on ovarian cancer and what has happened over the past year. We're going to talk first about newly diagnosed ovarian cancer, and then I'm going to pivot to patients with recurrent ovarian cancer. And I think some new findings have occurred, and I think some studies, which we'll talk about, have more questionable findings and may just need more time.

So PRIMA was presented at ESMO. Brad Monk presented at ESMO and then kind of a simultaneous presentation in the Annals of Oncology last year. And then certainly we were waiting for PRIMA OS results to come to really help us decide, do we use PARP inhibitors in everybody, specifically niraparib, where it currently has a full approval, or should we tailor the use of a PARP inhibitor based upon the HRD status? Then, FIRST, that just happened at ASCO 2025, comparing PARP inhibitor maintenance to PARP inhibitor maintenance plus an immune-oncology agent, specifically dostarlimab, in patients with newly diagnosed ovarian cancer in response to platinum-based chemotherapy.

And then the KEYLYNK trial that was presented at ESGO in a presentation and then SGO again as an oral presentation. We don't have a paper yet. And then an update on the PAOLA-1 trial. Just an interesting article from the International Journal of Gynecologic Cancer about PFS and OS based upon risk, risk of recurrence. Okay.

So the PRIMA study everybody knows. This is a trial of advanced ovarian cancer patients, high-grade serous, high-grade endometroid, in response to 6 cycles of chemotherapy. And they were randomized 2:1 to either niraparib versus placebo. And the primary endpoint here was progression-free survival. It's important to remember on all these studies where you think about survival is that subsequent PARP inhibitor use occurs. And that would only be natural, both in the patients who received a PARP inhibitor and then even in, obviously, the patients who received placebo. So for the niraparib treated group, even some of those patients were treated in the recurrent setting. But in the placebo group, specifically of those patients who have HRD present cancer, it was almost 50% of patients received subsequent PARP inhibitors. And just something to remember. Obviously, in the United States, the FDA approvals have been altered in the past 2 to 3 years where we can only use PARP inhibitors in the BRCA mutated setting, in the recurrent setting. But in the up-front setting, obviously, we can use, based upon PRIMA, niraparib for all patients regardless of BRCA status or HRD status.

So here are the very eagerly awaited overall survival results. And initially, overall survival was tested in the overall population. And that's an A in the upper left or the top curve. And that did not show any improvement from an OS perspective when niraparib was given. So formal OS analysis of the HRD population did not occur based upon the statistical section. And I think, so here, overall population is an A, really no difference. And then HRP over to the right, and then HRD to the below. And there's no improvement in overall survival. Even in the HRD, not even a trend towards OS improvement. Obviously, the trial was powered for progression-free survival, not for overall survival.

Now, I think it's very interesting when you delve in a little bit further, and these were not necessarily formally analyzed, but you can see the curves here. So the top curve here further OS is HRD-positive, BRCA mutated. And not much of a difference in the survival curve. And that is of interest because that's not totally what we saw with SOLO-1. All these trials do show progression-free survival benefits with the use of a PARP inhibitor, which is most pronounced in patients with an underlying either somatic or germline BRCA mutation. But there was a trend towards OS improvement in SOLO-1, which we're not seeing here. And I think that's an interesting finding.

So this is really the PRIMA OS results have really changed my practice. And I definitely have a conversation with patients who have HRP, homologous recombination proficient tumors. But because of the rather minimal progression-free survival benefit, and here we're not seeing any OS benefit, I am deprioritizing the use of a PARP inhibitor in the HRP setting.

Now, the FIRST study we just heard about a few days ago at ASCO 2025. The FIRST study initially had 3 arms to it. 1 was a standard of care arm, so just chemotherapy. Arm 2 was chemotherapy plus or minus bev followed by niraparib maintenance. And then arm 3 is chemotherapy plus dostarlimab plus or minus bev followed by niraparib and dostarlimab with or without bev. But due to the approval of niraparib in the first-line setting, arm 1 was closed and then participants were subsequently randomized 1:2 to either arms 2 and 3. In this trial, again, advanced high-grade serous, high-grade endometroid patients receiving carboplatin and paclitaxel. Primary endpoint here is investigator assessed progression-free survival in arms 2 and 3. And if PFS results were significant, then OS testing would continue. And there was a press release a few weeks ago saying that, yes, in fact, PFS was significant and that the results would be presented at ASCO. Interestingly enough, there was also a subset of patients with PD-L1 or HRD-positive and those with concurrent bevacizumab. These patients were identified a priori as a clinically plausible group to have kind of special or differentiated results.

So the next few slides show these results. So these are the progression-free survival curves. Median PFS was 19.2 months for niraparib alone. And then when adding dostarlimab, it increased a little bit more. It was about a 1.4 month median PFS improvement. Then when looking at the PD-L1 population, really not much of an improvement here. And this is the population that one might consider having additional benefit from dostarlimab. OS was also presented 57% maturity for OS and these curves are overlapping.

So I think in terms of the FIRST takeaway points, really essentially the same or relatively comparable progression-free survival benefits of adding dostarlimab compared to not adding dostarlimab, 1.4 months difference in the median PFS. There was no overall survival benefit of adding dostarlimab to niraparib maintenance. And that PD-L1 biomarker did not predict the impact of the checkpoint inhibitor. In this particular trial, patients could have received bev or not. About 50% of patients did receive bevacizumab. And I think as the paper comes out, one would want to see, does the receipt of bevacizumab influence therapy outcomes? Probably not, but it would be interesting to see.

Dr Graybill in the International Journal of Gynecologic Oncology actually looked at PRIMA. So FIRST, of course, hasn't been, is not in a paper yet, but PRIMA is. Dr Graybill did a post hoc analysis to determine the factors predictive of long-term disease for survival. And I don't think the findings were particularly surprising, but basically looked for progression-free survival 2 years or more. And essentially, HRD-positive cancers. I say HRD, so an HRD cancer, either BRCA1 or 2 mutated or BRCA wild-type HRD. FIGO Stage III versus IV, so perhaps slightly better outcome. And then 0 or 1 baseline nontarget lesions versus greater than 2. So, again, potentially better prognostic disease is going to predict for a longer progression-free survival. So interesting, but not too surprising.

The next 2 trials are other studies that have examined the combination of an IO agent with a PARP inhibitor. And I'll tell you my thoughts on all of this. But this is the KEYLYNK trial presented at ESGO and SGO. Again, advanced non-BRCA, this is non-BRCA specifically, mutated, newly diagnosed ovarian cancer, Stage III/IV, high-grade serous. The treatment arms are carboplatin/paclitaxel, second arm carboplatin/paclitaxel/pembro, followed by pembrolizumab maintenance. And then the third arm adds olaparib as maintenance to pembrolizumab with pembro added to chemotherapy. In this trial, all the arms could be given with or without bevacizumab. And there's no PARP inhibitor alone maintenance arm. And these are some of the results that were presented at ESGO specifically. The results really focused in on patients whose tumors had a CPS score of 10 or higher. And you can see on the right, there was interim analysis 1 and also the final analysis. And there's really not too much difference between the interim analysis 1 and the final analysis. And the significance threshold of pembrolizumab versus control in the CPS10 population was not met. And thus, formal testing of PFS in the overall population and OS was not performed. But on the right, you can see here, pembrolizumab/olaparib versus control was examined. And then at the bottom, pembro without the PARP inhibitor versus control was examined. And in terms of progression-free survival, adding the PARP inhibitor did improve progression-free survival; however, when it's just pembro alone, no PARP inhibitor, there's a trend towards a little bit of an improvement in PFS but the confidence intervals cross over 1.

And then DUO-O was another trial. This trial testing durvalumab. Here, advanced ovarian cancer, non-BRCA mutated patients, treatment-naïve, et cetera, 3 arms. Patients could have been randomized 1:1:1 either carboplatin/paclitaxel with bev, bev maintenance, carboplatin/paclitaxel/bev and then durvalumab added. And then the third arm, olaparib is added as maintenance. And again, there's no PARP inhibitor alone arm. And here, the 2 populations that were examined were the non-BRCA mutated HRD-positive and then the non-BRCA mutated intent-to-treat population.

And here are those results. There was an improvement in progression-free survival for arm 3. That's where the PARP inhibitor is added to the backbone of carboplatin/paclitaxel/bev plus durvalumab. But in terms of the arm that just added durvalumab, that, again, a slight improvement in PFS, but I don't think particularly clinically meaningful. And then the intent-to-treat population was pretty much the same increase in the PFS when the PARP inhibitor was added. But immunotherapy alone added to chemotherapy and then as maintenance really is having just minimal effect. We're not seeing a negative effect like we have with other trials, just not a particularly robust added effect here. And this is interim overall survival and really no differences here in overall survival at this time point.

So both of these studies do not have the control that one would consider for standard of care as having the PARP inhibitor as maintenance. So you can't really compare the trial to standard of care. And then based upon these 3 studies, FIRST, DUO-O and KEYLYNK, the data do not support adding an IO agent, at least I don't think, adding an IO agent to a PARP inhibitor as maintenance. And neither is there justification for adding a checkpoint inhibitor to chemotherapy or using that as maintenance therapy.

PAOLA-1, this was Ketta Lorusso's post hoc analysis in PAOLA-1. PAOLA-1 remember is patients receive chemotherapy with bev and then are randomized to either bev alone or a PARP inhibitor added to bevacizumab. And the patients are broken down based upon risk. So at higher risk were patients with Stage III disease who had up-front surgery and had residual cancer received neoadjuvant chemotherapy or had Stage IV disease. Patients with lower risk disease had Stage III and had up-front surgery and had a complete R0 resection. Most of the patients in this trial had higher risk disease three-quarters, 25% were lower risk. And in this particular trial, what Dr Lorusso found was that really there was a benefit of using the combination of bevacizumab and olaparib in really any patient with an HRD-positive cancer. And that's what the results have shown and that's where the FDA approval exists. And in the patients with homologous recombination proficient tumor, there is no benefit regardless of the risk of the type of patient that you're seeing. And there's not an indication here at all to use bev and olaparib in a patient with a homologous recombination-proficient tumor.

Moving on to recurrent ovarian cancer, lots to talk about here. Exciting results on avutometinib and defactinib. The ROSELLA trial, KEYNOTE-B96, just press released.

Raludotatug deruxtecan, and MIRASOL final OS results.

So this data has been presented many times. And I think it's really exciting data and is really an improvement for patients who have a RAS-mutated low-grade serous carcinoma. Rachel Grisham presented this at SGO. But it's been presented multiple times in different meetings. Avutometinib is a RAF/MEK clamp. So it blocks both RAF and MEK. And it prevents feedback reactivation from ERK back to RAF. And it also prevents stimulation of FAK. And through defactinib, there's also FAK inhibition. So it's a really pretty neat combination based upon the biology that is really driving a low-grade serous carcinoma cell that has an underlying RAS mutation. This combination was granted accelerated FDA approval on May 7^th and I think we'll be using this very shortly when it becomes available.

This is the RAMP 201 data, again that has been presented multiple times and has led to that accelerated approval. The number of patients is 115 through these blue. So the selection phase, expansion phase, and expansion phase combo. Of this dosing, on the bottom left here is avutometinib dose of 3.2. So patients will take four 0.8 mg capsules twice per week, so day 1 and 4, for the first 3 weeks of each 4-week cycle. And then they're given defactinib 200 mg twice daily for 3 weeks out of the 4 weeks. Other schedules were tested. So there was a lower dose combination and then there was just avutometinib alone and both of those really produced inferior results.

So these are some of the high-level results that have been presented and I'm sure we'll see in the FDA package insert and in a manuscript. But a very impressive waterfall plot. And we're seeing an overall response rate of 44% for patients who have specifically a KRAS mutation. So we also can see NRAS mutations in low-grade serous but here's KRAS mutation. For KRAS wild-type, the response rates are there but it is lower at 17%. That duration of response is pretty impressive. So for KRAS mutated patients, the duration of response is 31.1 months. For wild-type, it's 9 months. The median PFS, 22 months for patients who have a KRAS mutation in their cancer versus 12.8 months in KRAS wild type. So it's understandable why the accelerated approval is happening in the RAS-mutated part.

These are some of the results that Dr Grisham presented at SGO. And some of the factors that play into the level of response rates that patients are seeing. So here, the pink bars, are the RAS-mutated patients. So this is a prior MEK inhibitor, yes or no. And if a patient has not received a prior MEK inhibitor, the response rates are higher. Prior bev, if patients have not received prior bev, and this is also true of chemotherapy in ovarian cancer, response rates are higher. And then what we see with a lot of treatments, the more heavily pretreated patients, greater than 3, have 36% rate versus 49% for up 2 to 3.

Toxicities, 80% of patients had adverse events that led to dose interruption. A little over a third of patients had adverse events that led to dose reduction. About 10% of patients discontinued treatment because of adverse events. And the most common reason for this was an elevation of CPK. And that's found in a routine blood test. And both of the drugs seem to be able to lead to an elevated CPK. So great study. Terrific results. We're going to be using these. And I think really is a win for patients who have a KRAS mutated low-grade serous cancer. Really a major improvement in treatment.

The ROSELLA study was presented at ASCO and then had a simultaneous publication in Lancet. The glucocorticoid receptor, which is the subject of the study, is a nuclear hormone receptor and transcription factor activated by cortisol and then treatment with glucocorticoids. One of my former faculty at Dana-Farber, who is now at GSK, Jen Veneris, when she was at the University of Chicago, noted in some really interesting papers that increased glucocorticoid receptor expression is associated with decreased overall survival in ovarian cancer patients. It also seems to lower the ability for chemotherapy to be efficacious. And in vitro, what happens is that the glucocorticoid receptor activation inhibits chemotherapy-induced ovarian cancer cell killing and it's thought to occur because of transcriptional upregulation of anti-apoptotic genes. So that makes the chemotherapy work less. So by modulating or inhibiting that receptor activity in combination with chemotherapy may improve patient outcomes. So you're basically lessening that transcriptional upregulation with the antagonist of the glucocorticoid receptor. But then you're also adding chemotherapy that's now going to work better.

There was a randomized Phase II study that our group participated in and that was looking for different schedules of nab paclitaxel. And the reason nab paclitaxel was chosen was because it does not require steroid premedications. And 2 types of schedules were looked at. One was an intermittent relacorilant schedule where you give relacorilant 150 mg the day before, the day of paclitaxel and the day after versus continuous relacorilant versus nab paclitaxel monotherapy. And the reason that the nab paclitaxel dose was lowered here to 80 mg/m² when you combine with relacorilant is because of CYP3A4 interactions. And in this trial, the schedule I, so the intermittent relacorilant was chosen because it had better efficacy.

And that was moved into the ROSELLA study design. So this is a Phase III trial, unblinded, open label. And this is taken from the supplementary section in the paper. Patients on the top, this is the experimental arm, nab paclitaxel, 80 per m², days 1, 8, 15 out of a 28-day cycle, and then relacorilant day before, day of, day after, versus nab paclitaxel 100 mg/m². And that is the trial design. The study, basically if a patient had to come off one of these two drugs, it seemed, and I looked at the study very carefully in the supplementary section, it did appear that the patient would stop treatment. The patient wouldn't continue on nab paclitaxel alone if she had to come off relacorilant or vice versa.

So these are some of the statistics. So there was a dual primary endpoint, PFS, and with a 1:1 randomization, 230 events could show that the study had an 86.4% power to detect a 50% increase in progression-free survival. OS was allocated to a 2-sided alpha of 0.01 significance. And if that PFS null hypothesis were rejected, then the alpha would be tested at 0.05. So what we've seen here at the ASCO presentation and the paper is the interim analysis. So the interim analysis is interim. The progression-free survival statistics were performed per the stats plan. The OS was conducted at an alpha of 0.000 — three 0s — 1 and a formal OS analysis will be conducted later.

So these are the results from the paper. The PF was termed statistically significant. Hazard ratio was 0.45, 0.54 sorry, to 0.91, 0.7, with approximately a 1-month improvement in progression, median progression-free survival. OS, the curves look interesting, but this is all preliminary work. And these are interim analyses. And the log-rank p here is 0.01. Remember, it had to hit 0.0001. So it is not significant and is still very much preliminary.

These are some of the toxicities. So for dose reductions due to adverse events, nearly 50% of nab paclitaxel had to be dose reduced in the combination arm and about 30% in the monotherapy arm. There was a higher rate of Grade 3 or higher neutropenia and anemia. And in the combination arm, the rate of Grade 3 or 4 higher neutropenia was 44% and for nab paclitaxel alone, it was 25%.

So I do have some reservations about this study, and I think we'll have to really wait for the final results. This data represents an interim analysis. The OS benefit is not statistically significant. And the PFS benefit is a month. It's nonblinded, nab paclitaxel, yes, it's on the NCCN guidelines, but we do not use it standardly. It's higher toxicities compared to weekly paclitaxel. Similar efficacy, but I think more myelosuppression. No control over what patients receive post-treatment. There's really a mix of ovarian cancer histologies enrolled. So these are patients with high-grade serous, high-grade endometroid and carcinosarcoma. Kudos to the team for allowing carcinosarcoma, but we're going to have to see what the mix is in the 2 different populations. Based upon Jennifer's work, that level of expression of the glucocorticoid receptor seemed to be important in outcomes. But in this trial, we don't see a specific quantification, and it's not being used as a biomarker. As I mentioned already, there's a higher rate of Grade 3, 4 neutropenia and anemia in the experimental arm.

B96, I'm just going to say a few words about because we haven't seen anything. This is based upon a press release a few weeks ago. This is a trial predominantly done in Europe. Phase 3 randomized double-blinded trial of pembro plus paclitaxel, weekly paclitaxel, plus or minus bevacizumab versus weekly paclitaxel plus bev. And in terms of the eligibility, platinum-resistant ovarian cancer, up to 2 prior lines of chemotherapy. Primary endpoint here is progression-free survival by the investigator in patients with PD-L1, CPS 1 or higher, and in all patients as well.

These are the, well, I should say, planned accrual was 643 patients. The pembro dose is given on a 6-week schedule of 400. Paclitaxel here, 80 mg/m² per week on a 3-weekly schedule. Press release a few weeks ago showed that the trial met its primary endpoint of progression-free survival for platinum-resistant ovarian cancer, whose tumors expressed PD-L1 and in allcomers. And the study also met a secondary endpoint of OS in patients whose tumors did express PD-L1. And interesting results. We'll have to see the presentation in the final paper. When thinking back to KEYNOTE-100 that was published in the Annals of Oncology in 2019, and this was testing, first time we tested pembrolizumab alone in platinum-resistant ovarian cancer, and really also took a very deep dive into the molecular determinants and really couldn't find anything. But one clinical factor that did appear to be interesting was the CPS score looked at less than 1, 1 or higher, and then 10 or higher. And the response rates goes from 4.1% to 5.7 to 10%. So hence why that higher CPS score is looked at in ovarian cancer to determine if there's going to be more benefit.

Okay. Finishing up with a very exciting topic of antibody-drug conjugates. At SGO, Dr Van Gorp presented final overall survival results of MIRASOL. And this is, if you all recall, a Phase 3 trial of mirvetuximab, an antibody-drug conjugate, with a DM4 antimitotic payload against folate receptor alpha versus investigator's choice chemotherapy, weekly paclitaxel, liposomal doxorubicin or topotecan, up to 3 prior lines, FOLR1 positive. And then patients were randomized 1:1 to mirv versus investigator's choice chemotherapy, nonblinded. Primary endpoint here was PFS by investigator. Key secondary endpoint OS, duration of response, overall response rate.

And these are the final OS results, which stood up to more interim analyses. And there's a statistically significant improvement of overall survival for mirvetuximab versus investigator's choice chemotherapy. So an active drug in patients with recurrent platinum-resistant ovarian cancer, not heavily pretreated, up to 3 prior lines, who have a folate receptor alpha positivity.

And then Katie Moore presented data at SGO on raludotatug deruxtecan. That is an antibody-drug conjugate with a deruxtecan payload, Topo 1 payload, against CDH6. And certainly very impressive overall responses.

And this is regardless of the biomarker. So this is a drug that clearly has an advantage of, yes, it's very active and does not require a biomarker. And so this is a slide that she showed. The PRs are in purple. The CRs are in dark. Not many CRs. But you can see that on the left, the lower membrane intensity and there are definitely responses maybe slightly more towards the right. So definitely an active drug.

And then just talking about 2 other folate receptor alpha medications that have been tested in the recurrent setting, rinatabart sesutecan. This was data presented by my colleague Betsy Lee at SGO in 2025 looking at 2 different doses. Rinatabart, or Rina-S, the 120 and then 100 mg/m², showing a nice response rate of the 120 at 55.6% and then a slightly lower response rate in the 100. This is a drug that is moving on to the Phase III trial in the platinum-resistant ovarian cancer space that is not requiring a specific folate receptor alpha level of positivity.

Luveltamab tazevibulin is a medication that is an ADC, a mitotic payload, anti-mitotic payload that is currently in Phase III testing right now. And this is looking at 2 different doses. Basically, there was a press release a few days before SGO 2025 that said that Sutro was going to deprioritize luveltamab development. And then at SGO, these are the results. And you can see that the higher dose of 5.2 mg/kg had about a 32% response rate. And the lower dose, where patients have to go down to because there's definitely a significant amount of toxicity with this drug, there's only about a 14% response rate.

So these are the ongoing Phase II and III antibody-drug conjugates trials in ovarian cancer and this will continue to evolve with time. In the first-line setting, trastuzumab deruxtecan is being tested as maintenance. In the second-line platinum-sensitive setting, sacituzumab/tirumotecan, or Sac-TMT, is being tested. And then GLORIOSA and mirvetuximab. And in the platinum-resistant setting, all the drugs I've just mentioned. So luveltamab, tazevibulin, raludotatug, or raludo, is being tested against investigator's choice chemotherapy in the platinum-resistant setting. And then the rinatabart study, or the RAINFOL-OV2, is just opening. And this is, again, anti-folate receptor alpha, antibody-drug conjugate, Topo 1 payload, no biomarker needed. So really, the raludo and rinatabart are going to be kind of going head to head for a very similar population. So thank you so much. It's been a pleasure to update you on what's going on in ovarian cancer, and lots more to come over the next year for sure.

Endometrial Cancer and Cervical Cancer — Susana Banerjee, MBBS, MA, PhD

PROF BANERJEE: Hello, my name is Professor Susana Banerjee. I’m a medical oncologist practicing at the Royal Marsden Hospital in London, and I’m really delighted to be having this opportunity to give an overview of what’s happened in the last year or so in endometrial and cervical cancer. So much has happened, and in particular, focus on ASCO, which was earlier this year. So I’ve selected a few abstracts, some papers, which really I want to cover some take-home messages, things that are looking promising but also things that we have in practice, and looking at how we can integrate into practice now or whether things aren’t quite ready for prime time yet.

So I’m going to kick off talking about endometrial cancer. And here are some of the abstracts that I will cover. Immunotherapy has revolutionized the care of our patients in clinic, and it’s so great that we’ve got effective treatments now thanks to Phase III clinical trials. And we have a number of immunotherapy approaches now in the first-line advanced and recurrent endometrial cancer setting.

So today I’m going to mention the overall survival analysis from the RUBY study and also the NRG GY018 of pembrolizumab overall survival analysis. In addition to this, we’ll look at some patient subgroups looking at RUBY Part 2, which is looking at the addition of a PARP inhibitor, and also the DUO-E study of durvalumab with chemotherapy and then also the addition of olaparib. But what we’re going to focus on is some results from ASCO looking at the role, or potential role, of circulating tumor DNA.

I’m also going to talk about nonimmunotherapy maintenance therapy, because there is treatment and we need to develop treatments beyond immunotherapy or alternatives to immunotherapy. And so we’re going to look at the SIENDO study, which is a nonimmunotherapy maintenance approach, and changing direction, actually looking at some results of looking at molecular residual disease detection.

So let’s start with the RUBY study. Now this was a Phase III randomized double-blinded multicenter study. And this looked at dostarlimab, a PD-1 inhibitor, with our standard of care, carboplatin and paclitaxel or our standard of care, which is without dostarlimab. And then the important point is that the dostarlimab in the study was either continued as maintenance therapy or in the nondostarlimab arm, this was just placebo. So a key point is that patients were included that had Stage III or IV disease or first recurrent endometrial cancer. And carcinosarcoma as well as clear cell, serous and some mixed histologies were permitted. So patients needed to be naïve to systemic anti-cancer therapy or have a recurrence or progression more than 6 months after completing systemic anticancer therapy. So these are patients that we see every day in our clinic, and I just thought it was important to remind ourselves of the study design as this has changed practice given the approvals.

So FDA approval was in August 2024 and EMA, so European approval, was slightly later in 2025. And dostarlimab with carboplatin and paclitaxel followed by single-agent dostarlimab, so as a maintenance approach, in primary advanced or recurrent endometrial cancer is approved regardless of mismatch repair status. And what I’m highlighting here is the overall survival publication in Annals of Oncology in 2024. So this was almost 500 patients randomized. This was a second interim analysis with 51% maturity, and the key take home message is that the overall population, so regardless of MMR status, there was a statistically and clinically meaningful significant reduction in the risk of death. So that’s a hazard ratio, 0.69, with the addition of dostarlimab to our backbone of chemotherapy, carboplatin and paclitaxel, versus what was our standard of care, carboplatin and paclitaxel alone. So if you look at the median overall survival to put it into context, this was about 44, 45 months versus 28 months.

So there were further analyses, prespecified but exploratory, because in everyday practice we want to see MMR-deficient or MSI-high and also how we class endometrial cancer as MMR-proficient or microsatellite stable. So I’ve shown you here on these slides, looking at the risk of death was lower in the dMMR/MSI-high population. That’s very clear. The median overall survival hasn’t been reached there versus 31.4 months. And that hazard ratio is 0.32. But there is a trend also in favor of dostarlimab in that MMR-proficient population, so hence you see what’s been approved. This is really important when we’re counselling patients in clinic.

I’m going to move on now to the other practice-changing Phase III study of pembrolizumab, same sort of design in the terms of carboplatin and paclitaxel as our standard of care versus carboplatin/paclitaxel with pembrolizumab and continued as a maintenance therapy. What’s really important is that the primary endpoint was progression-free survival in the intention to treat, but also there were defined populations of the pMMR and also the dMMR population. And you can see the results here. The median progression-free survival was better, 13 months versus 8.7 months with a hazard ratio of 0.57 in the pMMR population. And in the dMMR population progression-free survival, median not reached versus 8 months or so in the chemotherapy arms. The hazard ratio is meaningful, 0.34, and clearly highly statistically significant. So this is what has changed our practice. And this is a secondary endpoint, which is immature, which is that overall survival I talked about in this publication. It’s an ad hoc analysis, but what we do see is the hazard ratio 0.57 in the MMR-deficient population and 0.8 in the pMMR.

So what we’re consistently seeing is that the magnitude of benefit is greater in the MMR-deficient population, but it’s also meaningful in the pMMR population and a step forward compared to carboplatin and paclitaxel. So I think this has been real progress in the field of first-line endometrial cancer.

So how do we build upon this? What else is going on in the trial arena and potentially then impacting on our practice? Well I just showed you RUBY Part 1 with dostarlimab. RUBY Part 2 looked at Stage III and IV patients in first recurrent disease, naïve to systemic therapy, so similar design or recurrence or progression more than 6 months after completing systemic therapy. Here the question is, dostarlimab with chemotherapy followed by dostarlimab with the PARP inhibitor, niraparib, versus the placebo with chemotherapy and placebo.

So I’m going to take a few moments just looking at that design. Primary endpoint progression-free survival by investigator. So here were the outcomes and the message here is, yes, there are statistically significant benefit in the MMR-proficient and also clinically relevant PFS difference in the MMR deficient. But I think the key question here is, what is the role, or how do we integrate a PARP inhibitor? There was no dostarlimab alone arm here in RUBY Part 2. So what is the magnitude of benefit with the addition of niraparib compared to dostarlimab alone, for example? So of course, we have some of that information from RUBY Part 1, but I think it’s very interesting to learn from Part 2 and also some of the subsequent subgroup analyses that we’ll see.

But let’s move on to another trial, a randomized Phase III study that also looked at the addition of a PARP inhibitor to immunotherapy. So the DUO-E study is published in the Journal of Clinical Oncology, and I’m just reminding you here of the design. I’m not going to go into too much detail, but really you can see it’s the same principle, chemotherapy, maintenance placebo, chemotherapy plus IO, durvalumab this time, versus maintenance durvalumab, or chemotherapy and durvalumab with durvalumab and olaparib. So note here, this is about the addition of a PARP inhibitor, but we don’t have a PARP inhibitor-alone arm.

And here you see the intention to treat population. There was certainly an improvement in terms of progression-free survival with the addition of durvalumab overall, and also in the overall population with olaparib. But then when we break this down further, we see that the greatest benefit with durvalumab versus chemo was in the MMR-deficient population, so consistent with what we’ve seen already with pembrolizumab and dostarlimab. And if we look in the pMMR population, what was interesting was to see that hazard ratio of 0.57 in the durvalumab plus olaparib arm. In the durvalumab arm alone it was 0.77. So this suggests that in the pMMR population, the addition of olaparib further enhances that benefit in terms of progression-free survival. This was published, as I say, already at ASCO this year. There was a post hoc exploratory analysis looking at longitudinal ctDNA. And I raise this because there’s a theme now looking at more trials currently and certainly at ASCO, about looking at the utility of ctDNA.

So a few bullet points here, looking at — these are smaller numbers. I didn’t go through how many numbers, but you can see on the slide it’s a small subset, but interesting signals. Baseline ctDNA positivity was associated with higher risk of progression whatever treatment you’ve received, whether it be chemotherapy with the IO or of the olaparib. Very interesting data there. And then if you look at this very nice analysis, I’d say, which is looking at changes over time of ctDNA and if we look in the pMMR population what we see is durvalumab or the addition of olaparib first could be driving activity in pMMR tumors, what we don’t see with durvalumab alone. Durvalumab led to more clearance of ctDNA and less of this rebound when you’re on treatment versus chemotherapy alone. And interestingly, the addition of olaparib to durvalumab led to 35% more clearance of ctDNA and less rebound, so reactivity if you like, versus chemotherapy alone.

So the key take away points by the presenters was that there clearly are changes with ctDNA. I’ve mentioned the less rebound that we can see with immunotherapy, and then potentially with addition of maintenance olaparib we can see further reduction of ctDNA. So in my view, this is very interesting, we need to look at this further in more patients. I don’t think it’s quite ready right now in our clinical practice, but you’ll see similar work on ctDNA in Gyn cancers in the remainder of the studies.

So moving swiftly on to non-IO maintenance. This is 1 study, which is looking at selinexor in the SIENDO study. So this is actually an inhibitor of exportin, so it’s a different approach, it’s not IO. And what we’ve seen in this study is that the patients with p53 wild-type tumors appear to derive benefit most. Now relatively small numbers as you can see here in terms of under 100 patients in that subgroup, but very interesting, nevertheless. If you look at the median progression-free survival in the p53 wild-type, 28 months versus 5 months.

This was published last year, and this is the progression-free survival in more detail. So the take home message for me is relatively low numbers but signal of interest. And there’s positive results in this subgroup analysis in this TP53 wild type and that’s regardless of MMR status there. And I think that’s a strong rationale for further evaluation as a maintenance therapy in TP53 wild-type advanced recurrent endometrial cancer, and there is the ongoing Phase III study now. But the real clinical question and trial question will be, in era of immunotherapy, how do we then integrate these results, or Phase III results, in an era of immunotherapy?

So changing direction completely, this is Stage I, so early-stage endometrial cancer, but I said we’d come back to ctDNA. This was an interesting paper about post-surgical ctDNA detection rates in patients with Stage I endometrial cancer. So what we see is that ctDNA is detectable. I appreciate small numbers, but you can see positive and negative and longitudinal changes. And the results essentially show that patients that were ctDNA positive at that first time point or at any point post-surgery, had significantly worse relapsed free survival compared to those women that had ctDNA-negative samples. And also that an increase in ctDNA levels pre- and postadjuvant chemotherapy or therapy identified patients experiencing recurrence. So it really is food for thought about serial ctDNA detection and we need to look at this further.

So there are limitations. This is retrospective, real-world short follow-up, but it also shows the value of real-world experience potentially to help them develop the right questions in the right trials. So prospective trials are required, in my view, for incorporation of how ctDNA is integrated. And what does that mean? Does it affect direct adjuvant therapy, escalation, de-escalation questions and maintenance therapy according to ctDNA status? So that was endometrial cancer, some highlights there.

And I'm going to move now on to cervical cancer. And we're going to look at recurrent disease, metastatic cervical cancer, so ADCs post first-line. We're also going to look at first-line advanced recurrent cervical cancer. And I'm going to kick off with 2 abstracts in that post first-line setting. And really, it's the world of ADCs now. So in cervical cancer, we're looking at tisotumab and I'll also talk about trastuzumab deruxtecan. And in the first-line setting, I'm going to mention immunotherapy.

So let's kick off with tisotumab vedotin in the second or third-line study. This drug is the first ADC to have FDA approval across gynae cancers and a very important study because we all know far too well how in clinical practice our treatments so far are not as effective as we need them to be. So patients were randomized to tisotumab vedotin or what we can use is chemotherapy as standard of care. And the primary endpoint was overall survival here. I was really pleased to be part of the trial team and a co-author on this New England Journal of Medicine manuscript.

So here are the practice changing data looking at overall survival as well as progression-free survival. And you do see an improvement in overall survival. Now, the issue is compared to many other cancers. So, clearly, this is statistically significant and clinically meaningful for this group of women where survival frankly is far too poor. But it's a step forward, but we need to do better. And the response rate really important with huge burdens of disease, tisotumab vedotin around 17, 18%, yet standard-of-care chemotherapy only 5%.

I'd like to mention here the importance of adverse events because ADCs are different to traditional chemotherapy and the side-effect profile is different. And what I want to highlight in particular for tisotumab vedotin as an ADC, that there are ocular adverse events, which we're not used to with traditional chemotherapy. So it's important when we're using this drug in practice to link well in with ophthalmology colleagues, risk of keratitis, risk of conjunctivitis, for example. So the hazard ratio is 0.7, so 30% reduction in the risk of death. And I've highlighted to recognize ocular toxicity. This is a step forward, but the prognosis remains poor and we need further improvements.

So that leads me nicely on to the DESTINYPanTumor study of trastuzumab deruxtecan. And to put this in context, based on this study, there's FDA approval for patients with immunohistochemical 3+ tumor agnostic. But of course, I'm focusing here on cervical cancer. And again, I could see firsthand as an investigator in this study the benefit to my patients with cervical cancer, also in the endometrial cancer arms and ovarian cancer arms as well. So, overall, the primary endpoint showed a response rate of 37%. And in patients with central HER2 3+ testing, the response rate was 61%, with a median duration of response 22 months.

Now, there were some patients actually in the cervical cancer arm that were also enrolled with 1+. So let's focus on cervical cancer here. For the IHC 3+ by local teams, response rate 80%, 2+ 40%. Now, this is really high. Small numbers in this study, I appreciate that, but we don't see response rates. I've just told you with standard of care chemotherapy in a prospective trial, it was 5%. So I think it's really important in clinical practice to do HER2 testing and if relevant offer this drug to patients. So this was single arm, relatively low numbers, positive signals. But you have FDA approval in this setting. And I do feel we also need prospective trials and those results across the world.

So now moving on to pembrolizumab plus chemotherapy for advanced recurrent cervical cancer. KEYNOTE-826.

So this treatment has revolutionized the care for our women with advanced and recurrent cervical cancer and really gives us hope about pushing the survival in this setting.

So what we've learned from here, because some patients have bevacizumab, but some patients can't have bevacizumab because of contraindications because where this disease is and risk of bowel perforation or fistulation. So what was really encouraging in this publication in Annals of Oncology this year was that, regardless really of bevacizumab use in the PD-L1 positive and the all-comer population, it was clear that the addition of pembrolizumab is helpful. So that's a really good take-home message that actually in patients both if they had bevacizumab or they didn't.

And similarly, so I just showed you progression-free survival, but also in overall survival. So we can comfortably counsel our patients about the benefits of pembrolizumab in immunotherapy first line with our chemotherapy, with or without bevacizumab.

So the final few moments, because I've concentrated on recurrent and metastatic disease, I'm going to mention some progress in locally advanced cervical cancer. So looking at KEYNOTE-A18. So can we actually bring forward the improvements we've seen in the metastatic recurrent setting, bringing some drugs forward? Could that actually be of benefit? So that's what the KEYNOTE-A18 looked at with pembrolizumab with chemoradiation in high-risk, locally advanced cervical cancer. And the final analysis results of the Phase III study were presented at ASCO. And with the theme that I've been talking about, I'm also going to talk about ctDNA analyses in cervical cancer.

So this was the KEYNOTE-A18 design. So I don't actually treat locally advanced early cancer, but I certainly see our patients in the multidisciplinary meetings and I can see how the need is there and what the benefit of this is. So this was Stage Ib2 to IIb, but also Stage III to IVa. And patients had chemoradiation plus external beam radiotherapy followed by brachytherapy plus pembrolizumab, continued pembrolizumab or placebo. And there's FDA and EMA approval based on these results.

So here's the primary endpoint. Progression-free survival at the interim first analysis. The hazard ratio, as you can see, is 0.7, with nice separation of the curves continued. And then this is the descriptive overall survival at final analysis. So a hazard ratio of 0.73. So I think that gives us confidence in considering pembrolizumab in this setting of locally advanced cervical cancer.

However, the CALLA study, which looked at durvalumab with chemoradiation versus chemoradiation alone, did not show a statistically significant improvement. But I think we can also learn a lot and that's the benefit of actually having further analyses and also translation analysis. So there was analysis according to ctDNA in terms of a marker of prognosis or indeed activity, because 30 to 50% of patients with locally advanced disease still have recurrent disease within 5 years after standard of care chemoradiation. So this study in terms of the biomarker analysis, I'm just showing you some aspects, very similar design, principle of chemoradiation plus durvalumab or placebo.

So I'm going to put everything on one slide and just talk through what the key results were. So ctDNA was detectable and the rates decreased after treatment and appeared lower with the durvalumab plus chemoradiation versus chemoradiation after 6 cycles. So it's important that we can detect this and it changes. Then we see that low ctDNA at baseline was associated with a reduced risk of both progression and death. Descriptive, I appreciate, and exploratory. And then, post-chemoradiation, ctDNA positivity was a negative prognostic factor for survival, progression-free and overall survival. And then, finally, what was interesting is that post chemoradiation, 68% of patients with ctDNA detected at cycle 3 day 1 subsequently progressed.

So the authors conclude that this supports the utility of this ultrasensitive tumor ctDNA analysis to help guide treatment decisions in the future. To put it simply, high baseline ctDNA levels increase risk of progression and death. Undetectable after treatment reduced risk of progression and death. So what's the next steps? How are we going to integrate this? And how can we integrate this, hopefully, prospectively into clinical trials? And I just want to take a moment talking about ctDNA because the assays have evolved over the years. And it is important to think about our limit of detection. But as assays become more sensitive or ultrasensitive, perhaps there is a role. We've seen this in other cancers at ASCO, for example, in breast cancer, colorectal cancer. But perhaps this is the time to look at this more closely in gynecological cancers. So my take-home messages are immunotherapy, change standard of care first-line, advanced, recurrent, endometrial cancer.

But we need to look at other maintenance strategies perhaps selinexor in p53 wild-type disease. ADCs, this is an era of ADCs, is changing the standard of care in cervical cancer. But our clinical trials currently there's a host of them in endometrial cancer as well. So watch this space. Tisotumab vedotin, T-DXd, all relevant now approved in cervical cancer. Bringing drugs earlier in locally advanced cervical cancer, pembrolizumab has changed the standard of care. And finally, ctDNA in endometrial cancer and cervical cancer is promising. So let's watch this space.