Current Management of Newly Diagnosed and Relapsed/Refractory Ovarian Cancer — Angeles Alvarez Secord, MD, MHSc

DR SECORD: Thank you so much for having me. It has certainly been a big year across the board for gynecologic cancers, and certainly for ovarian cancer, so excited to present some of the information regarding the management of patients who have newly diagnosed or platinum-refractory or -resistant ovarian cancer with really late-breaking data from this past year to inform us.

So my goals today are to discuss the management of patients with newly diagnosed ovarian cancer with a focus on patients who have epithelial ovarian cancer, review therapeutic options for patients with platinum-resistant and platinum-sensitive epithelial ovarian cancer and review the emerging landscape and novel therapeutics, which is really so exciting right now.

When we evaluate global cancer statistics the numbers are staggering, over 300,000 cases of ovarian cancer around the world, and you can see that really these cancers predominantly are across all of these different continents around the world, and you can see the high mortality rate, as well, compared to the incidence. So this is a global problem, and while there’s a high incidence of this disease in developing and developed countries there’s a huge burden on mortality in some of the countries that don’t have access to care and some of these novel therapies or surgeries.

And ovarian cancer care landscape has changed. We do know that a lot of patients are diagnosed with advanced disease. The typical backbone of therapy is paclitaxel and carboplatin-based chemotherapy with or without bevacizumab. We’ve gone through trying to figure out if we should do primary debulking first or neoadjuvant chemotherapy strategy with interval debulking. But those 2 things, the chemotherapy and the surgery, are 2 very important hallmarks to ensure that patients receive when they’re diagnosed with advanced epithelial ovarian cancer, and then at the end of that therapy evaluating patients who are candidates for maintenance treatment, either with bevacizumab or with PARP inhibitors or other options.

Unfortunately, a lot of these patients will recur, and it’s very sad when that happens, and when patients recur we still are kind of putting them into these 2 groups of platinum-sensitive versus recurrent disease based on that treatment-free interval from their last platinum-based chemotherapy. I do think that area is changing rapidly in terms of how we think of that, but for the purpose of this talk today I’m going to focus on those 2 buckets.

So patients with platinum-resistant disease have recurred in less than 6 months after they finish their chemotherapy while those with platinum sensitive recur greater than that 6-month period of time. For patients with platinum-sensitive disease typically it’s a doublet therapy with reinduction of platinum and consideration of a maintenance strategy. And then many of these patients will be able to get into another remission, but ultimately they’ll relapse again, either with platinum-sensitive disease or platinum-resistant disease. And for those with platinum-resistant ovarian cancer it’s very challenging with subsequent lines of chemotherapy. But what I’m going to share with you today is some very hopeful, hopeful findings in this arena.

So let’s talk about NCCN Guidelines for patients with high-grade serous cancer. High-grade endometrioid cancer is treated very similarly. I do think that in the future we’re going to be treating these patients with clear cell cancer and carcinosarcomas perhaps a little differently based on some of the novel therapies coming out, but for right now it’s really this paclitaxel and carboplatin-based regimen we talked about before with or without bevacizumab. But there’s a lot of other recommended regimens here with other doublets that you can consider in combination with platinum. And then in some patients there may be alternative strategies beyond intravenous therapy, like intraperitoneal therapy, and there’s so much interest in HIPEC with the heated intraperitoneal therapy at the time of surgery.

What about maintenance? Well, I remember being in that audience in 2019, and I think I shared with you all of the excitement of being at ESMO when they presented very pivotal studies regarding the use of PARP maintenance in patients with advanced newly diagnosed epithelial ovarian cancer. And these landmark studies just changed the way that we see treatment for select patients, specifically those patients who have a BRCA mutation, whether it’s a germline mutation or a somatic mutation, meaning mutation that occurs in the cancer, and then for patients who have homologous recombinant-deficient disease. We’ve gone through a lot of changes since these studies were first presented, with many kind of considering a PARP inhibitor strategy for all and moving more toward precision-based medicine, where we’re identifying patients most likely to benefit.

And this is just some of the latest data from those initial studies that were presented back in 2019. SOLO-1 has demonstrated really strong progression-free survival results and overall survival results, with a huge improvement in disease control in patients who have a BRCA mutation, as shown by that red line there in that figure. And you can see this story again repeating for patients who were enrolled on PAOLA-1, where they received bevacizumab and a PARP approach with olaparib, specifically for those patients who had BRCA mutations or for those with HRD disease, and those are shown in those 2 upper graphs in the middle.

And then again, for patients who were on the PRIMA study with a different strategy with niraparib in the maintenance setting showing that patients who have HRD/BRCA mutations or HRD/BRCA wild type have significant improvement improvements compared to placebo. Where we’re still struggling in terms of trying to identify treatments that make a difference are for those patients who have HRD-negative disease, otherwise known as HR-proficient, which gets a little confusing.

But what I think we’ve seen with updates from these trials, and these are the graphs that show the overall survival, is that for patients who have a BRCA mutation there is a striking improvement in some cases, where it’s a striking numerical improvement, I would say, in terms of disease outcomes and survival. And when I look at these — these lines, I think that this is a win for us. It doesn’t tell us the full story. There’s still room to work here, but for my patients who have a BRCA mutation, who have a newly diagnosed epithelial ovarian cancer, I am most definitely discussing and recommending a PARP inhibitor approach for those patients who are eligible.

Now, what about for patients who have HR-deficient disease that are BRCA wild type? There still appears to be a potential numerical benefit in many of these studies, but I think it gets — the lines get a little bit blurred, and we don’t really understand these patients as well. And there’s been so much talk about HRD not being a great marker, because it’s not a functional marker, but for right now it’s the best marker we have. But for patients who have HRD-negative or HR-proficient cancers there’s no improvement in overall survival.

So what about adding immunotherapy to patients who are getting a PARP inhibitor? And here’s some studies in this arena. And I would say that with the DUO-O study it’s an issue of the study arm, the patients who received the IO plus the PARP inhibitor had improved outcomes. However, they’re missing a critical arm with the PARP inhibitor only. And then the KEYLYNK study was a very interesting study also evaluating IO and olaparib therapy. And these are 2 different survival curves evaluating progression-free survival.

And you can see here the patients who had a certain CPS score of greater than or equal to 10, where there does appear to be some improvement, but again a really missing component in this study and understanding of the relative benefit of adding a PARP inhibitor to the immunology — or rather the immunology to the PARP inhibitor. And then recently we received study results from the FIRST trial.

I think collectively where I am in all of this — and this just shows the overall survival was not significantly different in the IO strategies with PARP inhibitors. The middle figure here for KEYLYNK I just wanted to show the stats because if you did not pass the statistical parameters with PFS then you could not really do a statistical or analytical assessment of overall survival. There’s been some really interesting data looking at biomarkers further in ovarian cancer that I didn’t go into today because it really would take us down a rabbit hole, but I put that there as a teaser if we ever want to talk about it.

So going back to NCCN Guidelines. It’s really to PARP inhibitor or not to PARP inhibitor. And while there’s a lot of different options in NCCN Guidelines I have really limited PARP inhibitor use in the maintenance setting to patients who have a BRCA mutation and then strong consideration to have that discussion with the patient about the potential benefit if they have HRD-positive disease.

And this is just the most recent updated FDA indications for olaparib and niraparib. And I am a biomarker person. I love biomarkers to direct therapy when they are helpful in identifying those patients most likely to benefit from adding the therapy, and also we want to make sure that we’re reducing toxicity and not exposing somebody to a treatment that may not help them. The challenging thing with PARP inhibitors is what’s the downstream effect, and we’re going to talk about that a little bit later when we revisit another study called PICCOLO.

I wanted to also point out ICON8B because there’s not a lot of people talking about this study, and I look at these results and I go — I feel like I’m on a ping pong table, there’s a ping pong ball, and you’re hitting it back and forth, because this is a question that we’ve gone back to numerous times now with the weekly paclitaxel data coming out of the Japanese study first, being evaluated in 262, the initial ICON8 study and most recently ICONB, with a study being positive, a study being negative but a subset group being positive, a study being negative, and now ICON8B being positive, where a weekly paclitaxel strategy was evaluated with carboplatin and bevacizumab.

And you can see here that there is an improvement in progression-free survival with this strategy compared to a Q3-week approach, and that improvement also transcended to an overall survival improvement of 10 months, so I’m asking myself do we go back to a weekly paclitaxel strategy in the front-line setting. We implemented this at one point when the studies appeared very promising. It does create some clinical challenges in terms of the treatment room and access to chair time. Our treatment rooms are full. I don’t know how things are at other places in the country.

However, I feel like I need to go back and talk to this about our group and talk about the potential benefits of going back to a weekly dose-dense paclitaxel approach in the front-line setting. Now, this will have implications for what may happen if patients then subsequently recur what treatment options you’re evaluating, but you can see here in the forest plots that this weekly approach tended to have improvements across all of these different patient characteristic parameters. So I’m very intrigued by this. I don’t think we’ve explored it enough when we have these conversations, probably, because it’s not a super-hot topic anymore. However, I do feel like we need to go back and have further discussion about how this fits into our treatment armamentarium.

Alright. So I want to get to this study because I think it’s really important. We talked about to PARP or not to PARP and which patients may benefit, and so that leaves us with this huge gap when you think about patients who are going to benefit from a PARP inhibitor in the maintenance setting. That’s probably about 50% of patients in our practice, so about 50% of patients won’t have BRCA mutations or HRD disease. What can we do for those patients? And there’s this whole wave of antibody-drug conjugates, like this one here, trastuzumab deruxtecan, or T-DXd, where they’re evaluating the benefit of this treatment.

This study design is with T-DXd with bevacizumab versus bevacizumab maintenance therapy in patients with HER2-expressing ovarian cancer, and I think these studies are really exciting looking at different treatment opportunities, incorporation of ADCs, whether it’s for the maintenance setting or in a front-line setting with different chemotherapy regimens. So stay tuned for these types of studies. It’s a very exciting study design.

And then now, let’s go to platinum-resistant ovarian cancer. This is the NCCN Guidelines. You can see there’s so many different treatments here, but how many of these treatments are really beneficial in this current era? I wanted to highlight the ones that I feel are really important. We know weekly paclitaxel is one of the best, if not the best chemotherapy regimen in the platinum-resistant ovarian cancer setting. I’m going to show you some data there.

And then in terms of targeted therapy we have bevacizumab, mirvetuximab soravtansine, those studies really changed the way that we approach patients with platinum-resistant ovarian cancer that we’ll discuss, for patients who have high-expressing folate receptor alpha tumors, and then immunotherapy for select patients. I don’t really see this as an option too much in patients with high-grade serous cancer. Most of these patients don’t have mismatch repair deficiency or MSI cancers, but it’s very important to look for this because these patients can benefit from an immunotherapy approach.

And then T-DXd for patients who have HER2-expressing cancers, and mirvetuximab with bevacizumab in certain patients who have FR-positive disease but maybe at a lower expression.

So this is an older study, the AURELIA study, and I think the investigators should be incredibly proud for putting this study together. This was an investigator-led study evaluating chemotherapy alone versus chemotherapy with bevacizumab. And what you can see here is that randomization that was standard of care or physician-choice chemotherapy versus a bevacizumab and chemotherapy strategy with either paclitaxel, topotecan or PLD. And the yellow line reflects the bevacizumab arm, with significant improvement in disease control, with a hazard ratio that was quite striking for the time, where you had a doubling of progression-free survival with the addition of bevacizumab. And overall survival was numerically improved with bevacizumab but not significantly different between these arms.

But what I want to point out is the paracentesis figure in the top right. I like this because I think clinically it makes a difference. Having paracenteses on multiple occasions or having a PleurX drain placed can be really a quality of life detrimental issue for patients who suffer from malignant ascites, and what this showed here is that the addition of bevacizumab to chemotherapy reduced the need for paracentesis quite dramatically. So I wanted to point that out.

The other thing I want to do is point out the weekly paclitaxel arm. I’m going to give a shout-out to Dr Dave O’Malley. He would talk about this at our meetings all the time, and I really wasn’t quite sure what to make of this data, where the weekly paclitaxel arm really did so much better than patients who received topotecan or PLD. But in my mind was that because of investigator-based bias or was that because patients who were on second-line treatment, where they’re most likely to do better, were more likely to receive paclitaxel than one of these other treatments? But what you see here is that the addition of bevacizumab to weekly paclitaxel led to a fairly dramatic improvement in disease control.

These patients had a PFS of about 10 months, which compared to chemotherapy alone was pretty striking, where it typically is in the 3-5-month range. And then overall survival was one of the longest overall survivals we saw at that point in time, which was 22.4 months, which was essentially unheard of.

But you have to be careful because some of these subgroup analyses are exploratory, but now we’re seen multiple studies in the Phase III setting where weekly paclitaxel has been a control arm where you see very similar response rates. And with the bar graph in the lower right you can see that the addition of weekly paclitaxel with bevacizumab yielded a response rate of over 50% compared to single-agent therapy, which was about 30%. And I also think this demonstrates that paclitaxel — that topotecan and then PLD, which is pegylated liposomal doxorubicin, really had a lot less activity than we anticipated.

I want to talk about MIRASOL really quickly. This was a huge game-changing study following on the heels of SORAYA study. The SORAYA study led to accelerated FDA approval, and this was a confirmatory registry Phase III trial which evaluated mirvetuximab compared to investigator-choice chemotherapy with either paclitaxel, PLD or topotecan. Very importantly, these patients had to have not only FRα-positive disease, but they had to have high expression, with at least 75% of their viable tumor expression — or their viable tumor cells having at least 2+ membrane staining. So this is pretty strict criteria in terms of the high expressing levels of FRα. But I will say, when I have a patient that’s in my clinic and they have FRα-high expression, I am status post excited because then I know that they’re a candidate for mirvetuximab.

And why am I excited? It’s because of this. So this is the most recent data presented by VanGorp and his colleagues at the SGO Meeting this past year and it demonstrates the updated survival data from this study showing that patients who received mirvetuximab had much better disease control than those patients that received investigator-choice chemotherapy. And I think it’s really important to note here that it’s not just the median survival outcomes here, but it’s really looking at that area under the curve that you see this benefit of mirvetuximab compared to the other chemotherapy options. And another really important thing to note is that this response rate was even higher than what they saw in the SORAYA trial, and so over 40% of patients are going to respond to this drug.

And the other thing I think that’s important — I didn’t go too much into the safety signals, but mirvetuximab has a very unique safety profile. We talk about the ocular toxicity, but for the most part that is mild, it’s reversible, but in terms of the other side effects that we see it’s actually fairly well managed. I have seen issues with fatigue and neuropathy. A lot of the neuropathy is really in patients who have pre-existing neuropathy, where you have to be careful, but that is the most common things I’ve seen. In North Carolina we probably see a little bit more pneumonitis than elsewhere, but it hasn’t been severe. So a really fantastic option for our patients.

Well, what about other antibody-drug conjugates? And I just want to mention, too, mirvetuximab was the first-in-class antibody-drug conjugate that we had in our armamentarium, which I like to see these ADCs as heat-seeking missiles, where they’re latching on to that protein, inserting the most potent chemotherapy payload, which has just been such a dramatic improvement for our patients.

But there are other ADCs out there, and this other one is T-DXd, or trastuzumab deruxtecan, for patients who have HER2-positive cancers. The FDA approval is for patients with 3+ protein expression, and this is based on IHC, and it’s gastric scoring, which is very important because it’s — the breast cancer scoring that sometimes you receive clinically is a little bit more rigid than the gastric scoring. And the NCCN Guidelines include not just 3+ but also 2+ expression.

And another study I want to point out is the PICCOLO study, which was a Phase II trial — I was so fortunate to be able to part of this study. It was a wonderful experience — for patients with platinum-sensitive ovarian cancer. It’s really important to note that patients with platinum-sensitive disease, now that we’re doing more maintenance, I think that we see more patients with platinum-sensitive cancers, when you have reinduction platinum opportunities, it may not be the same response rate that we used to see prior to the use of PARP inhibitors. And so we’ve seen a little bit of change in the tumor biology, and I feel like this was an important study to address a very important, urgent patient, unmet need, and that is for novel therapies in patients with heavily pretreated platinum-sensitive ovarian cancer.

So this was a Phase II study. About 80 patients were enrolled. They had to have high-expressing FRα-positive cancers, and they were treated with single-agent mirvetuximab. Now, if they had a BRCA mutation they had to get treated with a prior PARP inhibitor, and prior bev was not required, but many of these patients received prior bev. At the time when this study was developed, in terms of the statistical analysis, we did not know what the right benchmark was, which seems crazy now, right? But at the time we didn’t know what the expected objective response rate should be for patients with platinum-sensitive ovarian cancer in a PARP inhibitor era.

And this Medidata analysis that’s shown here, that’s data that we had after the fact. But it was really intriguing data that was presented by Dr Rob Coleman last year that they did a Medidata pooled analysis for patients who had third line or higher platinum-sensitive ovarian cancer. And 97% of these patients had a PARP inhibitor, many progressing on PARP inhibitor, and the objective response rate was only 17%, which is so much worse than what we think we’re going to see based on older data. The median progression-free survival in this Medidata pooled analysis was only 6 months, and the median OS was about 20 months.

So let’s go forward now. Let’s talk about PICCOLO data results. This is the waterfall plot on the left, which shows that almost every single patient on the study, except for 2, had clinical benefit. The confirmed investigator-assessed objective response rate was 51.9%, the median duration of response was over 8 months, and the median progression-free survival was about 7 months. Now, this was a heavily pretreated group. Almost all of these patients had had a prior PARP inhibitor. In fact, only 12 patients hadn’t been previously exposed to PARP. Exposure to bev was over 50%. Exposure to taxanes was very, very common in the first-line setting; it was 57 of those patients. Multiple lines in 20 patients. And the most recent platinum-free interval was less than or equal to 12 months in 43% of patients.

So a lot of information here in terms of this heavily pretreated group. And when you evaluate the objective response rate in the overall population, as I mentioned, it was 51.9%, but there was a big difference in terms of these PARP subgroups. And you have to be careful because these are exploratory analyses, but in the PARP-naïve group the response rate was 75%, which is phenomenal. Now, if they received PARP, and they progressed on a PARP, the response rates dropped down to 45.8%. And if they had prior PARP treatment but hadn’t progressed — or if they had any prior PARP treatment it was 46.9%.

The median duration of response ranged anywhere from 7-8 months, and the overall survival, here at the bottom, similar in all of these groups, was about 27 months, and that’s highlighted in the figure over there, and 77% of these patients received subsequent therapy. But the PICCOLO study really changed how I approach things for patients with platinum-sensitive heavily pretreated disease, and it’s included in the NCCN Guidelines as an option.

Let’s also talk about mirvetuximab and pembrolizumab for patients with PROC. We are still trying to find immunotherapy options for patients with this disease, and we’re going to talk about some immunotherapy incorporation for patients with platinum-resistant ovarian cancer as part of this discussion as well. This was the FORWARD II study that was presented by Matulonis this past year. Patients were treated with mirv and pembrolizumab. This included patients with low-expressing FRα cancers, as well as high.

And the exciting news here is that they did see acceptable efficacy here across these groups, and I’m going to show that in this next slide with this waterfall plot. This is really a beautiful color scheme here, but low is blue, medium is green and then high is red. And you can see that there’s objective response rates in all of these groups of patients regardless of their FRα expression levels, as long as it’s positive. The objective response rate was 31%.

You see these really nice spider plots here showing that some patients derived quite a long benefit of therapy. The median progression-free survival was only 4.2 months. But again, this is a very complicated group of a variety of different patients based on their biomarker.

And then the treatment-emergent pneumonitis was about 25%, but it was only Grade 3 or higher in 4% of patients. But pneumonitis is something we need to watch for, definitely.

T-DXd I already talked a little bit about in terms of the NCCN Guidelines. This was the ovarian subgroup. Small patients here, so we have to be a little careful about how we assess this data, but you can see these pretty amazing response rates compared to standard of care therapy, especially for those patients who had 3+ disease, where the response rate is over 60%. Super exciting. Median progression-free survival up to 12.5 months for those patients with IHC 3+ disease, and median OS is 20 months, so for patients who are HER2 3+ positive I am always thinking about T-DXd.

In terms of the safety summary with T-DXd, when I’m using this drug for my patients in clinic I want to really be careful about their bone marrow toxicity, neutropenia, and also monitoring lung function closely for pneumonitis.

And all of these exciting ADCs are emerging in the field, including T-DXd that we’ve talked about, but also R-DXd that targets cadherin-6 and Rina-S and AZD5335 targeting FRα, HS-20089 targeting B7-H4 and then TUB-040 targeting NaPiB2 — or NaPi2b. And across all of these you see response rates that are blowing traditional chemotherapy out of the water, ranging anywhere from 23 to 64%. So exciting time as we embark on seeing this wave of ADCs. I’m going to look forward to next year when I get to give more information about those.

And then we can’t forget these drug combinations for patients with low-grade serous cancer, avutometinib/defactinib. I actually have nicknamed this avifac because it’s so hard to say both these together. Shown here is the study schema for patients with recurrent low-grade serous ovarian cancer. There was a lot of different cohorts here. Patients were evaluated based on whether they had KRAS mutations or wild type.

The treatment’s very interesting, and you have to do a lot of counseling in terms of when to take these medications and the timing of therapy, but the bottom line here from this waterfall plot is you can see this huge response rate, this is in patients who have KRAS mutations, demonstrated by that dark blue there, which was 44%. If patients had KRAS-wild-type disease there was still some evidence of response at 17%, as manifested by those teal lines. And then really durable progression-free survival here.

So exciting time with a novel therapeutic combination. The avutometinib is a first-in-class agent that’s really a clamp, if you will, targeting the RAF/MEK clamp and doesn’t allow something else to bind to it, which allows it to have more durable responses. It is important to understand the side effect profile here very carefully in terms of a rash, visual side effects, and mitigation strategies and also following closely for patients who have elevated LFTs and CPK levels. But a very exciting time, and FDA granted accelerated approval of avutometinib/defactinib in patients with KRAS-mutated recurrent low-grade serous ovarian cancer.

So in conclusion, a lot of exciting things happening this past year across the board. I think we’ve really honed in on which patients are most likely to benefit from maintenance PARP inhibitors and really trying to identify other options of exciting new therapies and ADCs for patients who are not candidates for PARP inhibitors in that front-line setting. And then mirvetuximab has changed the field of care for patients not only with platinum-resistant ovarian cancer but platinum-sensitive ovarian cancer, so important to make sure that you are checking for FRα expression and identifying patients who may be a candidate for this first-in-class antibody-drug conjugate.

We’ll see how mirvetuximab is combined with other therapies in the future, similar to what I showed you with the pembrolizumab data, and if we can expand the benefit of mirv to patients who have lower levels of FRα expression, promising new therapies for ADCs that are now in Phase III trials, and I share some of that data in the table, and then of course new therapeutic options for patients who have low-grade serous ovarian cancers. And the RAMP 301 confirmatory trial has currently completed enrollment, and we’re so excited for the results of that study.

Thank you so much for having me. I know this is a whirlwind of data that I presented, but we’ve seen these transformative changes in how we care for our patients, which is really exciting.

Promising Novel Agents and Strategies Under Investigation in Ovarian Cancer — Nicoletta Colombo, MD

PROF COLOMBO: Good day to everyone. It is my pleasure to review some promising novel agents and strategies under investigation in ovarian cancer.

I will be focusing mainly on what nowadays we call platinum-ineligible ovarian cancer. What does it mean? This is a recurrence, and for these patients we do believe that platinum is not the best option. In the past we would call this platinum-resistant ovarian cancer, but nowadays we prefer this term platinum ineligible.

As you can see, there are several strategies now under investigation to treat patients with relapsed, platinum-ineligible ovarian cancer. The first one is I would like to overview is the use of antibody-drug conjugates. As you know, there are so many antibody-drug conjugates now under investigation, and I just will go through some of them. This will not be a complete list because, as I said, there are very many under investigation.

So first of all, let me talk about the folate receptor alpha ADCs. Mirvetuximab is the first one approved in ovarian cancer and is an FRα ADC, but this is not the only one. We do have at least 3 more FRα ADCs currently under investigation in ovarian cancer.

The first one is what we call Rina-S, which is an FRα ADC with a highly hydrophilic linker and a payload which is a TOPO1 inhibitor. In the Phase I/II but with dose expansion of this RAINFOL trial, RAINFOL-01, 2 doses of Rina-S were investigated in patients with ovarian cancer, 100 mg/m2 and 120 mg/m2. Patients were heavily pretreated, up to 5 prior lines of therapy, and the response rate was very impressive because you can see with the dose of 120 mg/m2 particularly the confirmed overall response rate was 55.6%. And these responses were seen across also different levels of expression of the receptor, of the FRα receptor, so this, of course, is very interesting.

And as you can see, the duration of response also is very long. And in terms of toxicity profile Rina-S was well tolerated, with primary cytopenias and low-grade GI events, but no signals of ocular toxicity, neuropathy or even ILD were observed. And this, of course, is very, very interesting.

So the RAINFOL-02 is a prospective, randomized, Phase III in patients with platinum-resistant ovarian cancer. The key eligibility criteria included patients with 1-4 prior lines of therapy and treatment with all of the following: platinum chemo, bevacizumab unless contraindication, PARP inhibitor if BRCA mutated and mirvetuximab if folate receptor alpha-high expression and available in the region. So that’s very important. The patients had to have measurable disease according to RECIST 1.1, folate expression must be available, and participants may be enrolled regardless of folate receptor alpha expression. That’s very important. So you don’t need expression of folate receptor alpha to be included, but in case the tumor has high expression of folate receptor alpha the patient must have received mirvetuximab before.

And they are randomized to receive Rina-S 120 mg/m2 day 1 Q3 weeks or investigator choice chemotherapy, PLD 40 mg/m2 every 4 weeks or paclitaxel weekly or gemcitabine or topotecan. Risk stratification factors are geographic regions, number of prior lines of therapy and prior mirvetuximab and folate receptor alpha status. And the primary endpoint is progression-free survival per investigator with key secondary endpoints being overall survival, overall response rate and other secondary endpoints like safety and duration of response and so on. The trial is currently ongoing both in the US and in Europe.

Another FRα ADC which is currently under investigation is AZD5335. Again, it is FRα-targeting with a TOPO1 inhibitor payload. And the trial, which was presented at ESMO, is the FONTANA trial. This is a Phase I looking at different doses of this compound, which is also called torvu sam. And as you can see, again, a very high response rate was observed across different doses of this compound. Overall, the response rate is 53.6% in heavily pretreated patients.

The TREVI-OC-01 trial is a randomized Phase III study with torvu sam (AZD5335), again in platinum-resistant ovarian cancer. Key eligibility criteria include platinum-resistant ovarian cancer, 1-3 prior lines of therapy, prior bev and PARP inhibitor are allowed, and no prior mirvetuximab or TOPO1 inhibitor ADC. Why? Because actually in this trial there are 2 different groups of patients.

In the case of folate receptor alpha high, we will randomize 550 patients to receive AZD5335 or mirvetuximab, so this is a direct comparison of torvu sam compared to mirvetuximab for patients in which the tumor presents a high expression of FRα. For the other patients with folate receptor alpha low expression, patients will be randomized to receive AZD5335 or investigator choice chemotherapy; paclitaxel, PLD or topotecan. Here the primary endpoint will be progression-free survival by investigator, and the key secondary endpoint will be overall survival. The trial is currently ongoing already in the US and hopefully will also start in Europe very soon.

Another interesting FRα drug, ADC. This is the initial results from a first-in-human Phase I study in advanced ovarian cancer. Again, you see a response rate around 50% with a long duration of response, and a Phase III, called FRAmework-01, is currently ongoing also with this compound, comparing this ADC compared to standard of care chemotherapy.

So these were the 3 FRα ADCs, but of course there are other targets which are important. First of all, this claudin-6. This is highly expressed in ovarian cancer, up to 85% of epithelial ovarian cancer. And the drug we are discussing is raludotatug deruxtecan, or R-DXd, which is a CDH6-directed ADC comprising of an antibody and with a TOPO1 inhibitor.

This study is called REJOICE-Ovarian01. As you see, it’s a complex design. There was a Phase II part of the study looking at 3 different doses of this drug in patients with ovarian cancer, platinum-resistant ovarian cancer, and then, of course, a Phase III is currently ongoing.

The results of the Phase II dose finding were presented at ESMO last year by Dr Ray-Coquard. And again, as you can see responses were seen across different doses of this drug, but actually the dose of 5.6 was chosen because of the toxicity profile and efficacy.

And here you see, in fact, the toxicity profile of this drug. This is the dose that has been chosen for the Phase III. The most common side effects were nausea, anemia, asthenia, neutropenia. This was seen across all doses, but as I said, comparing the efficacy and the tolerability the dose of 5.6 mg/kg was chosen for this Phase III.

And this is the Phase III, which is currently ongoing, comparing R-DXd compared to standard of care chemo, gemcitabine, PLD, topotecan or weekly paclitaxel.

A very interesting subgroup analysis of the REJOICE study was presented at ESMO GYN last year by Katie Moore, and this is a subgroup of patients with platinum-sensitive relapse. This was only 18 patients, which were treated inside the REJOICE-01. And as you can see, the responses in this population were quite interesting. You see here the majority of these patients had a response, 72.2% response rate, but also an analysis was done on patients progressing on PARP inhibitor who were treated with this drug.

Why is this important? Because, as you know, it’s really emerging, the problem of the platinum resistance for patients who are progressing during the PARP inhibitor treatment. And so we need probably other forms of treatment for these patients. So this drug, as you can see, even in patients with progression during PARP inhibitor, was able to provide a very high response rate of 58%. So this can be seen in the future as a possible drug to be used in this context.

Moving to a different target, this is the NaPi2b, and this is another very interesting ADC targeting NaPi2b. The results of this Phase I were presented at ESMO last year by Dr Gonzalez. Two different doses were chosen.

And as you can see also the response rate was quite impressive, 59% overall response rate across different doses of this drug. Also, the onset of activity was seen at very low doses. Complete responses were also observed, and CA-125 response in 81% of these patients. And 93% of responding patients were ongoing at the time of presentation. 80% of patients remain on treatment, indicating a durable benefit. So also for this drug a Phase III study is planned comparing standard of care.

So as you see, there is really what I call a tsunami of ADCs in ovarian cancer. Many of them are used. Unfortunately, the majority of these ADCs have the same payload. And this, I think, in the future will be a big problem because of course typically if you use an ADC with this TOPO1 inhibitor payload it will be difficult to use again another ADC with the same payload.

So I think a lot of work has to be done. Of course, we have to understand better about the target, the level of expression, predictive biomarkers. We have to understand that payload, the bystander effect. We need to understand the partner. Should we use this drug alone or in combination? Combination with chemo? Combination with targeted therapy? Which is the best setting to use this drug? In the platinum resistant, platinum sensitive or even in front-line because there are also now trials planned in front line, particularly in the HRD-negative population.

Now, I want to move to a completely different strategy, and this is the cell cycle regulation and DNA repair. This is very interesting because, as you know, this is the cell cycle. The cell cycle is regulated by the checkpoint. The checkpoints are very important because they slow down the cell cycle to allow for DNA repair.

So in many of our tumors, particularly high-grade serous ovarian cancer, we lose 1 of these checkpoints, the p53 checkpoint. So the idea is to block another checkpoint, and in this way we will increase the replication stress, and we will move the cells to a mitotic catastrophe.

So this is done by using some of the checkpoint inhibitors, and one of these is selective CDK2 inhibitors. This is the compound. And these results were presented at ASCO last year. As you can see, it’s a CDK2 inhibitor in platinum-resistant and refractory ovarian cancer, and particularly in the presence of the cyclin E1 amplification or overexpression you see a response rate of 33.3%. So also this compound will probably go to a Phase III in the near future.

Immunotherapy. So we have been trying for many years to improve the results with immunotherapy in ovarian cancer. We have wonderful results in cervical cancer and in endometrial cancer. Unfortunately, in ovarian cancer we were not so lucky.

And actually there were a lot of trials, all of them negative, in different settings front-line, platinum sensitive, platinum resistant, so we thought the game was over, but indeed that is not the case because, as you know, as I presented at ESMO last year, the results of the ENGOT-ov65/KEYNOTE-B96 study. This was a study for patients with platinum-resistant ovarian cancer with 1 or 2 prior lines of therapy, and they were randomized to receive pembrolizumab or placebo together with chemotherapy, weekly paclitaxel, with or without bevacizumab. And the stratification factors were the use of bevacizumab, the region and the PD-L1 expression. And the primary endpoint was progression-free survival per RECIST, and the key secondary endpoint was overall survival.

At the first interim analysis in the population with a CPS score of 1 and higher there was a statistically significant improvement in progression-free survival for patients treated with pembrolizumab compared to placebo, with a hazard ratio of 0.72. As you can see, at 12 months there were 55% of patients progression free compared to 22.6% in the placebo arm.

And here is the results in the intention-to-treat population, also in the overall population we see an improvement in progression-free survival, with a hazard ratio of 0.70. And as you can see, the median progression-free survival was 8 months in the pembro arm and was 6 months in the placebo arm.

Even more important is the overall survival results. At the interim analysis 2 we were able to demonstrate in the CPS 1 and higher population an improvement in overall survival, with a hazard ratio of 0.76. The median overall survival was 18.2 months in the pembro arm and 14 months in the placebo, so it’s a 4-month improvement in overall survival. And I want to stress the performance of the control arm in this study because, as you can see, many other studies where weekly paclitaxel was only 1 of the several arms utilized in the control the median OS was much lower. But here we have a very high-performing control arm, with a median OS of 15 months, and yet you see a 4-month improvement in overall survival with the addition of pembrolizumab.

And as you know, it was announced that now the overall survival results that I’m going to present in 2 weeks at ESGO I will show also an improvement in overall survival in the intention-to-treat population, so not only in the CPS 1 and higher population but also in the overall population.

But when we talk about immunotherapy it’s not only about anti-PD-1 or anti-PD-L1, of course. There are also other forms of therapy, of immunotherapy, which are emerging. And I want just to mention the T-cell engagers like ubamatamab, which is a bispecific antibody targeting both the T-cells and also the tumor cells. So this is very important because it is designed to bridge MUC16 on cancer cells with CD3-expressing T-cells to facilitate T-cell activation and cytotoxicity.

Again, at ESMO last year, the results of this study. This is a randomized Phase II study of this ubamatamab plus or minus cemiplimab in patients with platinum-resistant ovarian cancer. What I want to stress is that the response rate may not be very impressive with this drug, but what is impressive is the duration of response. As you can see, very, very long-lasting. So this could be really an ideal drug to use in the maintenance setting, and this is something that hopefully will be planned very soon.

Finally, I want to mention another important strategy. This is relacorilant. What is relacorilant? It’s a novel selective glucocorticoid receptor antagonist that restores the sensitivity of cancers to cytotoxic chemotherapy. Why? Because cortisol actually may activate the expression of genes, which interfere with apoptotic pathway that many drugs use, for instance, taxane. So by using these glucocorticoid receptor modulators may restore the sensitivity to — particularly to taxane, and so the cytotoxicity may be increased.

This drug was first tested in a Phase II study and now in the Phase III ROSELLA trial. The results were published in Lancet last year. Here you see how relacorilant significantly improved progression-free survival, assessed by blinded review compared to control, and also there is a trend for overall survival. But again, the results on overall survival will be presented very soon in the complete — in the overall population, and hopefully they will confirm this trend that you see here for an improvement not only in progression-free but also in overall survival with the addition of relacorilant to weekly nab-paclitaxel.

So this is also an important subgroup analysis of the ROSELLA trial. Here you see how relacorilant may improve progression-free survival assessed by BICR. In the subgroup of patients who received prior PARP inhibitor treatment, again this is very important, we need drugs, very effective, when patients progress on PARP inhibitor. And as you can see also in this population the addition of relacorilant to nab-paclitaxel provided an improvement in progression-free survival, and this, of course, is true not only for patients who had received prior PARP but also for patients who progressed during PARP inhibitor. So again, this is a promising drug to be used or combination to be used for this specific population.

So just to conclude, I think ADCs are the new standard in platinum-resistant ovarian cancer because mirvetuximab was approved, as you know, but only in tumors with high folate receptor alpha expression. T-DXd also is approved by the FDA in HER2-positive 3+.

Other promising ADCs. You’re seeing the claudin-6-targeting ADCs, the Phase III is ongoing. There are new FRα-targeting ADCs and Phase IIIs are ongoing, including low or no folate receptor expression and also post mirvetuximab sequence, that’s very important to see. New targets include NaPi2b, claudin-6, B7-H3, B7-H4 and others, which are not shown to you, but they are also there.

And multiple Phase IIIs are ongoing and planned, both in platinum resistant, platinum sensitive and maintenance, restriction in prior platinum-resistant lines, limited but shared targets and payloads, TOPO1 inhibitor, so sequencing data are needed. We need to understand how to sequence all of these new drugs.

Beyond ADCs, 2 new drugs that may change clinical practice are relacorilant and pembrolizumab. Approvals are awaited. And once again unclear treatment sequencing, but we have to work on that.

And I thank you for your attention.