Introduction: Overview of Ovarian Cancer (OC) Management

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is Part 7 of an 11-part series that we’re doing here at the ONS meeting. We’ve been coming here for the last 17 years, and we always have the same format: 2 physicians and 2 nurse practitioners. Today we’re going to be talking about the very exciting area of ovarian cancer.

We have a great faculty today: Ms Courtney Arn from The Ohio State University in Columbus; Ms Jennifer Filipi from the Massachusetts General Hospital Cancer Center in Boston; Dr Dave O’Malley from The Ohio State University and James Comprehensive Cancer Center; and Dr Shannon Westin from the MD Anderson Cancer Center in Houston.

As in all of these programs, we will be discussing the use of unapproved agents and regimens, so consult the package insert for various agents for more specific information.

We are recording these programs, and we’ll let you know by email when they’re ready to go, but we’ll also be distributing it through a relatively new podcast series we started called Oncology Nursing Update. Just take your phone, go to podcasts, hit search, type in Oncology Nursing Update, and we already have a couple programs there, including one on bispecific antibodies. We’ll talk more about that tomorrow night in our lymphoma session.

As I mentioned, we’re doing 11 programs here, and in addition to talking about the specific cancers there are a number of themes that we’re getting into this week that kind of go into oncology nursing in general. And we really view this as sort of a rounds immersion experience here. We just really love the opportunity to work with this faculty, most of whom we’ve worked with before. It’s just such a pleasure to be able to query them, pick their brains, and learn a little bit more.

So with that by way of introduction, here’s where we’re heading. We’re going to chat a little bit about ovarian cancer and take a look at a case to begin, and then we’ll get into the idea of genetic testing for advanced ovarian cancer, PARP inhibitors, which is of course one of the biggest stories in oncology in general, including ovarian cancer, but really has taken a leadership role. We’ve already talked about PARP in our prostate session, in breast cancer as well. Then we’ll talk about some new therapies. Actually, in the faculty room I just heard about another therapy that just, apparently there was a press release just came out, so I’m curious to hear about that. We’ll hear about other new agents.

We did a session — the first session we did here Wednesday afternoon was on antibody-drug conjugates, and we’re going to talk about one of these at the end here, mirvetuximab soravtansine. If you weren’t here on Wednesday, again, you can check it out online.

So just a couple of words to kind of get started here in terms of an overview. And Shannon, when I think about ovarian cancer, at least from our perspective in education, things really started to ramp up just around 2018 I would say. Before that it seemed like we were just talking about chemotherapy, bevacizumab, surgery. And of course in 2018 we learned, and then we saw the data presented by Dr Katie Moore, of the first Phase III of many Phase III trials, a number of Phase III trials looking at PARP inhibitors. This was the SOLO-1 trial looking at olaparib.

And just to get started, I’ll just ask Shannon maybe to comment a little bit on kind of an overview of how — we just came back from — our group went to the Society of Gynecologic Oncology Meeting recently in Seattle, and it was, to me, really amazing how gynecologic oncology’s changed really since that time. Can you kind of provide a little bit of an overview, Shannon, of before and after 2018?

DR WESTIN: Yeah. I mean, I think you nailed it already, right? Before 2018 everybody was getting the same treatment, paclitaxel and carboplatin, regardless of histologic abnormalities, genetic and genomic abnormalities, and I think the SOLO-1 study, and then the subsequent PRIMA study and PAOLA-1 study that Dr O’Malley’s going to discuss, really exploded and gave us such an opportunity to be more thoughtful around what targeted therapies we might use, how we can improve patients’ lives with maintenance strategies. So not just stopping after 6 cycles of therapy and saying okay, good luck, and we’ll hope your cancer doesn’t come back, even though we know 80% of the time it will. We now have a little bit more directed options.

But, as we’ll talk about in the genetic portion, not everybody has the predictive biomarkers that would indicate PARP is going to be helpful, and so we were struggling a little bit with the other abnormalities and what to do with the patients that don’t have those. And I think what’s really blown up, and we’ll talk about this in Module 4, is this idea around antibody-drug conjugates, where we can use protein expression, which is much more common in patients with ovarian cancer, to direct a more targeted therapy. So it’s been very exciting.

DR LOVE: So Dave, another thing that’s kind of interesting about ovarian cancer, in a way it kind of reminds me of — yesterday we did a program on prostate cancer, where you have both medical oncologists and urologists involved. And here we have gynecologic oncologists and medical oncologists.

It was interesting, we did an entire program, and Dave ran it, at the SGO Meeting on HER2-positive gynecologic cancers, the antibody-drug conjugate T-DXd. And this had already come into medical oncology practice in breast cancer. They were already used to using it. Now all of a sudden the gynecologic oncologists are using it. And we went out and did videos with a bunch of community-based oncologists. I was amazed. They had come up to speed. They were using T-DXd.

Again, I’m just kind of curious about this interface between medical oncology, gynecologic oncology, Dave, how you see that playing out both in an academic center like yours, but also in the community. Like how does it determine — it seems like more and more sophisticated drugs are being used. Where do you see that playing out?

DR O'MALLEY: Well, I think it’s quite different regionally. In Boston the medical oncologists almost always deliver the chemotherapy, the Gyn oncologists do the surgery, and they collaborate. Many of our institutions, like my own and Shannon’s, we do both. And I love that because for one, I’m ADD, so if I get bored with the medical I go to surgical. But we appreciate the limits to both of them. But it is a lot when you’re also having the surgical expertise, and some people have decided it’s too much for me, I’m going to partner with a medical oncologist to deliver the care.

In the community, where many of you work, is whatever comes through the door you’re going to see, so keeping this all straight across all of that, I am not smart enough. I have trouble with my 3 cancers. I couldn’t imagine doing what many of our community oncology — does to try to keep up on this. So it is an education when you have new agents and thank goodness for programs like this.

DR LOVE: And Jennifer, it also brings up another theme in oncology, again we talk about themes, which is interdisciplinary collaboration. We talked about gynecologic oncology and medical oncology, but there are so many other disciplines that can be involved in terms of imaging, ophthalmology. We’re going to talk about ophthalmic issues. Any thoughts about how that plays out in the community, again, versus at an academic center like yours?

MS FILIPI: Yeah. I think in ways it’s the same. You can find the people that you want to collaborate with, whether you’re at an academic center or in the community. For example, and we’ll talk about this a little later, but with mirvetuximab we partnered with ophthalmologists, and I literally just cold emailed people and got some yeses, and thank goodness we did because there are a lot of side effects that we’ll talk about. But you can do that in the community, too, and even sometimes the pharmaceutical reps will go out to the eyecare centers and be able to give a little overview of that.

DR LOVE: Yeah. Yesterday we were talking about some of the newer agents in breast cancer that cause glucose intolerance. It’s been a while since oncologists dealt with diabetes in that level of detail. Last night we were talking about Bruton’s tyrosine kinase inhibitors and all the cardiologic effects, so it’s more and more an interdisciplinary endeavor.

I just want to kind of bring up a patient. This is actually a patient of Courtney and Dave’s, a patient in her 50s who had ovarian cancer. Maybe you can talk a little bit, Courtney, about how she presented and how that compares. And maybe we can just chat a little bit about how these people present and the initial experience they have with this disease.

MS ARN: Yeah. Speaking of the community, she presented to her local emergency room with abdominal pain. They did a CT scan that showed bilateral pelvic masses. They drew tumor markers and showed that she had an elevated CA-125, and then she was referred to our office, and Dr O’Malley did her surgery. Was found to have advanced ovarian cancer and received adjuvant chemotherapy.

DR LOVE: How was her surgery, Dave?

DR O'MALLEY: Well, we really get most of the disease out, all what we could see or feel, so she had a complete cytoreductive surgery. We spent a lot of time making that decision, should we do neoadjuvant versus primary. Her CT scan appeared that we would be able to get all of the disease, an R0 resection, and so we did proceed with primary debulking surgery in this scenario.

DR LOVE: How do you make that decision, Shannon? It seems like there are more and more ideas of using neoadjuvant chemo, sometimes with bevacizumab, particularly in patients with ascites or effusions. How do you decide whether to go right to surgery or give preop systemic therapy?

DR WESTIN: Yeah. I mean, I think David kind of got at the idea of where is the disease, right, because the goal of cytoreductive surgery in this setting is to remove all evidence of disease. We have very clear data around that. And in the past we didn’t know if neoadjuvant was as good as cytoreductive surgery, but now we have data to say, randomized controlled trials that say it is. And so we can be a little bit more selective.

So outside of things like disease that I know I can’t remove, we also look at patient factors, right? What’s her performance status? Is she going to be able to tolerate surgery? Is there any reason that we think it would be ideal to give that chemotherapy first? And I think we’re seeing more and more that that’s happening.

DR LOVE: So Courtney, it looks like she got a strategy that’s often used, and it looks like very successful. We’ll see the curves from the data from the trial and what a difference it is in a patient like this to get a PARP inhibitor or not. That was what was so revolutionary, what happened in 2018. I know Katie said when she saw those curves she could barely believe it. It was really amazing to look at.

So she got chemotherapy with typically used carboplatin/paclitaxel. She did not get bevacizumab. She went on 2 years of olaparib. And I’m curious, Courtney, how she tolerated the — and how she tolerated the olaparib and also maybe a little bit about her. One of the themes we have here is why was it different to take care of this patient than another patient in the same oncology situation but a different person. Different attitude, social situation, et cetera. Can you talk a little bit about this woman and what made her different and how she tolerated treatment?

MS ARN: Yeah. While receiving chemotherapy we referred her to our genetic counselor, and we found out that she had a BRCA2 germline mutation, so immediately we started talking to her about our plan for maintenance therapy. And you want to start this conversation early. You don’t want to wait until they finish their 6 cycles of chemotherapy to start the conversation of what their maintenance therapy will be.

So we started talking to her about it early on. As soon as she finished her chemotherapy we started the maintenance olaparib. She completed 2 years. She tolerated it really well, with minimal side effects. She did not require any dose modification. She completed her 2 years. She’s currently no evidence of disease for 3 years now since completing maintenance therapy.

Something interesting about her is she was adopted, so that made her genetic testing a little bit more interesting than some of our patients. She had really good family support, which I think helped get her to her appointments, helped with her tolerance of treatment. She also had a stroke at a young age. She had some residual left-sided weakness, but otherwise she was doing okay, but that impacted her care a little bit as well.

DR LOVE: Interesting. Interesting that she was adopted. And Jennifer, of course, typically in patients with germline mutations you start thinking about the family. We’ve had plenty of cases of patients, I remember a patient with pancreatic cancer, which we’re going to talk about Saturday — no, tonight, actually, who unfortunately passed away but was found to have a BRCA germline mutation. I think the daughter was also found to have BRCA positive, was able to undergo preventative surgery and avoid having breast cancer, also the same thing with prophylactic oophorectomy.

Any thoughts? Any comments, Jennifer, about how you see the issue with the family playing out? Do you see some patients who don’t want to be tested, they don’t want to have to kind of tell their family that this has happened?

MS FILIPI: I do see that. I think that’s more rare, thankfully, and oftentimes we’re able to kind of, not persuade, but let people know the importance of it. I have one patient that’s coming to mind. She has a BRCA1 germline mutation and has twin girls. So she’s doing fabulously. She had actually recurrent disease, and she’s on a PARP inhibitor currently. At the time of presentation PARP inhibitors didn’t exist. So now she’s 5 years on a PARP inhibitor, and we’ve kind of watched the twin girls grow up, and they’re in their 20s now and will get tested, I think, probably closer to 30.

DR LOVE: That’s interesting. So they held off on the testing because it wouldn’t change anything.

MS FILIPI: They did. Yeah. And you can kind of understand that. They see their mom go through this awful thing. I could see it go either way. But they will get tested.

DR LOVE: Another theme is patient involvement in decisions. When it’s not clear exactly what the best course is it’s always good to ask the patient if they want to be involved in the decision.

Genetic Testing for Newly Diagnosed Advanced OC

DR LOVE: So we’re going to start out now and talk about genetic testing and just testing in general in ovarian cancer. Again, another major theme in oncology, biomarker-guided therapy. You see this in almost every cancer and hematologic cancer, looking in the tumor for clues as to what kind of therapy, particularly some type of more targeted treatment. So Shannon, let’s talk about ovarian cancer in terms of testing.

DR WESTIN: Absolutely. So yes, I’ll be discussing the genetic testing component in newly advanced diagnosed ovarian cancer. And this is the course. I’m not going to go through this slide in detail. It’s a bit of level setting. And you just heard this case from Courtney where this person kind of followed the playbook of what we typically see at diagnosis. And of course as we’re making decisions around what to treat the patient, when to do surgery, the big thing and the big opportunity that we have, and the big opportunity to intervene, really is with that genetic testing.

Now, I want to make sure just we’re all on the same page about what mutations we can see. So germline mutations are going to be things that are passed through the family, and the entire organism is going to carry that mutation, versus somatic mutations, which can be very important clinically in how we treat the patient, are really only affected in 1 area, so in this case our ovarian cancer. So I think that’s really an important way to distinguish when we’re talking about the different tests.

Now when we talk about the potential for genetic mutations in ovarian cancer and those that really portend the most risk of ovarian cancer, BRCA1 and 2 are obviously the highest risk. Those are the most common, occurring in about 15 to 20% of all patients. But there’s other factors in the DNA damage repair pathways, what’s called homologous recombination repair pathways, that can be really important in both patients having ovarian cancer and also in the way that we might treat their ovarian cancer, and those include more rare mutations, but important, like RAD51D, RAD51C, PALB2, BRIP1. These are all really relevant. And then of course Lynch syndrome is also incredibly important. Now that’s where we see more commonly colorectal cancers and uterine cancers, but ovarian cancer can be seen in about 15% of those, and those are mutations that are in the mismatch repair pathway, such as MLH1, MSH2, MSH6, PMS2 and EPCAM. And the bottom line is all of the oncology groups agree everyone with ovarian cancer, epithelial ovarian cancer should undergo genetic testing.

Now I’m not going to go through this in as much detail, but it’s just to kind of let you know that there are other potential aberrations in the patient’s tumor that may impact not only cancer risk but also treatments that they can receive, the PARP inhibitors that we’ve discussed. And really up to 50% of patients with ovarian cancer may have some abnormality either in their germline or in their somatic tumor that can predict benefit from those very important drugs.

But first, if we identify a germline mutation, not only it is important for the way we’re treating our patient, but it’s also important for their family. We know that when there’s a germline inherited mutation it’s a 50/50 chance for first-degree relatives to also have that mutation, so with the opportunity for cancer prevention like we talked about in those 20-year-old twins, and screening for early detection both in family members, as well as in the patient themselves.

And unfortunately, even though we’ve known this for a long time, even though we have these great treatments with PARP inhibitors, we’re still not doing our best. This was a meta-analysis from 2021, and unfortunately I suspect the numbers aren’t very different, where only 40% of patients were being referred, and of those only 30% were actually completing genetic testing. So there’s a huge opportunity here to intervene and make an impact on the patient and her family. And unfortunately what we did see, in addition to just boldly across the board not having high numbers, that it was worse in under-represented minority populations, in those patients that don’t have prior insurance. So there’s a huge opportunity to make an impact here.

And so we can do a couple of different testing paradigms for ovarian cancer, whether we get the germline first, whether we get somatic tumor testing first and then prompt germline test if that’s positive. Regardless, we need to get these tests, and really we’re also looking for other ways to identify homologous recombination deficiency. Now that’s not going to be as important for family, but that’s going to be very relevant for patient and for what treatments that she might receive.

And so I don’t have the time to go through every different test, but this is just meant as a reference for you. There are tests that offer that HRD testing irrespective of mutations, that looks at things like loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions. The bottom line is this makes the tumor potentially responsive and sensitive to PARP inhibition. And you can get this through tests that only offer that, or what we like to favor is getting it where we can also get next-generation sequencing, where we can do a really deep dive on that patient’s tumor and look at the genetic abnormalities there.

And now I’ll just mention just briefly, moving on to the next — Dr O’Malley’s going to talk a lot about the use of PARP inhibitors. We also have to decide early on about the use of bevacizumab. At our institution we’ve really been favoring that for patients that test negative for everything else, because I have a hard time not giving a maintenance to somebody with ovarian cancer, and if I don’t feel as good about giving say PARP inhibitors in a patient population that tests negative, I like to use bev there.

And so I think I’ll stop there and thank you all for your attention.

DR LOVE: So just a couple follow-up points. You were talking about Lynch syndrome, and you can also see the same abnormality without it being genetic, MSI-high disease. And the important thing is from the point of view of the patient, these patients' tumors are extremely sensitive for immunotherapy, excellent responses that you see throughout oncology.

I was flashing back to last night when we were talking about prostate cancer, because there PARP inhibitors are very prominent, and they were saying that the men are trying to figure out why they’re positive for BRCA, a breast cancer mutation, but you see it not just in women or in breast cancer, but also prostate.

Jennifer, another thing about the comments about genetic counseling. The pandemic really revolutionized what we do because of the acceptance of Zoom, and now it’s like amazing what we’re able to do in education. I’ve been kind of disappointed. I was expecting it to be infiltrated more into clinical practice. There have been a lot of obstacles to that, particularly in terms of genetic counseling. Are there services online where you can — without having to go in to see a patient?

MS FILIPI: There are, and it probably varies institution to institution. We do something really cool at Mass General. Our genetics team is doing a study where patients are given iPads, and they’re taken through different levels of genetic testing with just the BRCA genes being 1 panel, a moderate panel, and then test everything that you can panel. And it takes them through this, and then at the end we as the team do all the work of sending off the blood and getting the results back. And if there’s a positive result, or if the patient does want to see the genetic counselor, at that time we can refer. And that just saves the genetics team time because they are such a coveted resource right now.

DR LOVE: Yeah. That’s a great concept there because to focus on the people who are positive, let the primary providers provide an intro and then try to get these patients — or at least certainly offer them genetic counseling.

Role of PARP Inhibitor Maintenance in Newly Diagnosed Advanced OC

DR LOVE: Alright. Let's move to — we’ve talked about testing, and interesting that it’s not just an issue for the patient, which we’re talking about today, but also for the family. But Dave, let’s talk about a situation like your case that we just presented, a patient who’s found to have a BRCA mutation, we’re saying germline, but really whether it’s germline or somatic it seems, at least in terms of response, to be very similar. The patient gets 6 cycles of chemo, just like your patient did, and is about to start PARP maintenance.

So we asked you to talk about some of the clinical research studies that led to this strategy, what the impact is. This patient you have now who’s been free of disease for several years now, what would the likelihood overall without PARP inhibitors? Would she be free of disease at this point?

DR O'MALLEY: The 15% plus/minus 5% across time. 15% plus or minus 5%. Unbelievably consistent. And so meaning — and if your disease recurs you died of ovarian cancer.

And as we look here in the results, from a PARP inhibitor in the first-line setting, and we’ll talk about this, Shannon and I have talked a lot about this over the years, is you need to use your best therapies early on.

So this is a little bit different than what Shannon presented from the NCCN Guidelines. This is adopted of the big decisions we have to make. We talked them already, neoadjuvant, okay, first versus primary debulking. Bev no bev. And then maintenance. And then maintenance. And I agree with you, Shannon, in my world, when I talk to these patients, it’s no longer are we going to do maintenance, but which maintenance should we do. So put that into context. And this is some of the references that we would go through in talking about this.

And how do PARP inhibitors work? Well, it’s the DNA repair mechanisms in the cells, and it disrupts that. And cancer cells, they don’t want to die, and so if we can get them to have abnormalities, and then abnormalities become a second abnormality, then the cell dies, synthetic lethality. So we’re messing around with the DNA repair of the cells. Cancer cells don’t die, those cells, and so when we introduce these changes then the cell dies, and that’s how we think PARP works. And we heard from Shannon, but it probably has multiple different ways that it does work.

We’ve already referred to SOLO-1. This was the drop the mic. This was the trial that looked at BRCA mutations. It was somatic or germline, but almost all patients, except for 6, had germline because we weren’t doing somatic testing at that time. Two years of PARP inhibitor, in this case olaparib, versus placebo in a 2:1 randomization.

And I’ve included here the most updated survival. In this case it was time to subsequent therapy, first subsequent therapy. This is a surrogate that you never recurred. And now look at those numbers, 7 years, 84 months. 45% have not started on a subsequent therapy or have not died. We went from, remember when I said 15% plus or minus 5%? I didn’t lie to you. It’s still 20% versus 45%.

And at the same time — not at the same time. Subsequently then we said well, if it works in BRCA it should work in other patients. And so we then did a trial with all comers. And a little higher-risk population. Instead of 2 years now 3 years. Once again 2:1 randomization, but now this is with niraparib rather than olaparib. Once a day, a little bit different, and Courtney’s going to talk more about the dosing.

This was the primary analysis in the tumor marker-positive test that Shannon referred to, HRD-positive. And you see the differences between those curves. You don’t have to be a statistician to say those are clearly different.

But what we wanted to see is we wanted to say okay, but we enrolled everybody. So going from left to right we have the BRCA mutation patients, then we have the patients in the middle that were not BRCA mutated, were not BRCA mutated but had HRD-positive, and then on the far right were HRD test negative, or negative biomarker. You see that those are more modest.

We were worried a little bit about the impact on overall survival. We don’t have time to get into it, but PARP inhibitors may change how the tumor behaves. And so this was just reported this year showing there’s no difference in overall survival. We would have liked to have seen an advantage, but because of crossover, with about 60% of patients who didn’t originally get a PARP getting a PARP, that’s probably diluted out, and we can talk about all day, and that’s exactly what we do do.

PAOLA-1 was the only trial that had an active comparator. So it’s olaparib again, but instead of going against placebo it was olaparib plus bev, as Shannon alluded to, the antivascular therapy bevacizumab, it’s hard for me to say bevacizumab, so I say bev, okay, versus bev alone. Alright? I can sit here and say bevacizumab and I sound like a dinkle. But alright. And again, we’re looking at 2:1 and for over 2 years for the olaparib, 1 year on the bev, okay?

And here we go again. This is the updated survival that Isabelle Ray-Coquard presented a couple years ago at a meeting. Look at 5 years recurrence, 46% have not recurred at 5 years versus 15% plus/minus 5%, 19%, and that’s with bev. Bev doesn’t curious more patients, it helps the disease from coming back so that shows here.

Now, how about when we’re trying to compare apples to apples? So I put this slide together, and I just took the BRCA patients, and I looked at their survival advantage. And you see in SOLO-1, in the upper right-hand corner, clear differentiation — PAOLA-1 in the bottom right, clear differentiation of survival, but what was the difference there? PARP inhibitors were not available for crossover, and so we see minimization of that overall survival when we start giving PARP inhibitors in subsequent therapy.

So I started off this talk by saying in my mind it’s no longer if we give maintenance, but which maintenance do we give, but let’s not forget our goal, curing patients. Curing patients, alright? We need biomarkers in all these patients, and we need to manage toxicity. I’m looking forward to Courtney’s talk about toxicity. Thank you.

DR LOVE: So I think it’s also important, we were talking last night about what we call the pelican curves, where it’s so wide apart it looks — and you don’t see that here. 46% is great, but there’s still patients who are recurring, so we still have more to go. Shannon, one of the things we’ve done a lot is do short videos to distribute. And I have a video of you from our SGO Meeting that I use that in 30 seconds I thought summarized where PARP is now. Because it takes a while. This started in 2018. It took several years to sort it out, think about it. We were doing tons of education programs, particularly about this — patients without a mutation, because initially there’s some suggestion niraparib was going to work in those patients, and it seems now with more follow-up maybe it’s not as exciting.

But you basically said the algorithm in 30 seconds that we saw ended up, which is if you’ve got BRCA, whether it’s somatic or germline, if you’ve got the LOH test that’s positive, you’re getting a PARP inhibitor. We can talk about which one or whether to add bev. And if you don’t, maybe you’re more likely to get bev. Anything you want to add to that, Shannon? And also the question, again, practically speaking, when do you add bev to a PARP inhibitor?

DR WESTIN: Yeah. I mean, I think the first question is when do you use bev at all, right? And so I think that the data that we’ve seen, we see an improvement in progression-free survival but not overall survival when we add bev to chemo. This is irrespective of BRCA, irrespective of PARP.

And so there was really mixed, I’d say, usage. Some groups used it for everybody. Some groups were a little bit more selective. I know our group definitely was more selective for those patients that had say Stage IV disease or had really bulky upper abdominal or a lot of ascites, a lot of fluid that we wanted to dry up with bev. Now, though, if we haven’t started bev with chemo up front, and then we’re getting our testing, and we’re getting an idea that our testing is all negative, right, no BRCA, no HRD, we’re adding bev outside of standard of care, but I think a lot of places are doing this. We’re adding bev then, and we’re saying okay, this is a patient that has HRD test negative. We don’t really feel great about giving them a PARP inhibitor alone in this setting. Let’s give a drug that we know is active. Let’s give bev. So we may add it on, layer it on a few cycles in.

DR LOVE: It’s interesting, too. You all really led the way in terms of PARP inhibitors. This week, when we did our prostate program, as well as breast, everybody was saying yeah, well it was the Gyn people that really figured out how to use it, the tolerability issues, and then when breast and prostate and pancreatic came along we learned from you.

And Courtney, of course one of the big issues was how to get people through the treatment, 2 years, and then niraparib 3 years. In oncology we’re seeing more and more use of novel agents, oral agents for a longer period of time. In breast cancer we’ve been doing that for a long time with hormonal therapy. But in order to get the benefit you want the patient to get through the therapy.

So let’s talk a little bit about some of the issues that may or may not come up with these patients and how you deal with it, Courtney.

MS ARN: Yeah. So now that Dr O’Malley’s explained why we should be giving PARP inhibitors and to who I’m going to explain the nursing considerations for the patients who are receiving a PARP inhibitor.

Prior to patients starting PARP inhibitor you want to meet with them, do a thorough patient education as far as what to expect as far as the most common side effects, symptom management, what their schedule’s going to look like. We do a lot of video visits at our institution so they don’t have to come in every single month, and then we typically bring them in every 3 months for convenience.

You do want to get baseline labs prior to starting treatment to make sure their labs have recovered from chemotherapy before starting the PARP inhibitor. And then you also want to make sure that their PARP inhibitors approved in a timely manner, too, so start looking into that before they’ve completed their 6 cycles of chemotherapy and applying for financial assistance if needed.

Dr O’Malley explained how PARP inhibitors work. When I’m talking to patients I try to simplify it as much as I can, and I essentially tell them that PARP inhibitors block the activity of PARP enzymes, which disrupts the normal DNA repair process and ultimately causes cell death, specifically for patients who have the BRCA mutation. And then I kind of lead into their BRCA results and why we’re giving them a PARP inhibitor and explain that tumor cells that carry a BRCA mutation have been shown to have significant sensitivity to the PARP inhibition compared to tumors that do not have the BRCA mutation.

The most common side effects for niraparib are thrombocytopenia, anemia, nausea, fatigue, neutropenia, constipation, musculoskeletal pain, hypertension. And the warning and precautions include MDS/AML, which we’ll talk about in a minute, hematologic hypertension, PRES and embryo-fetal toxicity.

The most common side effects we see with olaparib are nausea, fatigue, abdominal pain, vomiting, anemia, diarrhea. And then again, the warnings and precautions include MDS/AML, pneumonitis, VTE and embryo-fetal toxicity.

As you can see, there are a lot of overlapping side effects with the niraparib and olaparib. When I’m talking to patients I really focus on fatigue, GI side effects and the hematologic toxicity.

Early intervention is really important, so educating your patients on what to expect but also giving them precautions of when they should be calling. What we found is the earlier we intervene or hold treatment to allow their symptoms to improve we’ve definitely been able to keep patients on the same dose longer.

For patients having nausea, or if you have a patient who had a lot of nausea with their prior treatment, you might want to recommend doing a scheduled antiemetic 30 to 60 minutes before they take their PARP inhibitor to try to prevent nausea. For patients who are doing that and still having nausea throughout the day I usually put them on a schedule like BID dosing of an antiemetic, and sometimes even like 3 times a day or 4 times a day, depending on how bad their nausea is. You have to remember that these PARP inhibitors are daily dosing, and so it’s not like chemotherapy, where they might have 3 to 4 days of nausea. If they’re having nausea with the PARP inhibitors it’s often every single day, so have them take it first thing in the morning or 30 to 60 minutes before their PARP to try to prevent it.

Constipation’s another common side effect. If patients have constipation put them on a bowel regimen with stool softeners, laxatives, but also conservative with increasing fluids, increasing physical activity, talking about diet to help with it too.

Some patients have diarrhea, and in that case you’d want to do a scheduled antidiarrheal. Again, it’s daily dosing, so some of these patients have to take an antidiarrheal. I have them take it first thing in the morning when they wake up, before the diarrhea kicks in, to try to prevent it. If the patient’s having diarrhea you want to make sure they’re increasing their fluids, talk to them about a bland diet. Sometimes we have to give IV fluids, replace electrolytes. Keep those things in mind because they are at risk for dehydration if they’re having diarrhea.

As far as fatigue, make sure your patients are well hydrated, increasing their physical activity. We’ve seen huge benefit with referring our patients for physical therapy, and then also sometimes we consider using stimulants for our patients who have fatigue.

And then lastly, because of the hematologic toxicity, you want to make sure you have a plan in place of how often you’re checking the labs and having someone review them. We do weekly video visits for the niraparib when they require the weekly CBCs to make sure that their counts are okay and they’re okay to continue treatment. And then transfuse as needed.

This goes over the Grade 3 or higher AEs of special interest of the clinical trials that Dr O’Malley just talked about. The most notable for this is you can see the niraparib had Grade 3 anemia, neutropenia and thrombocytopenia, and then the bevacizumab and olaparib arm and the bevacizumab and placebo arm had Grade 3 hypertension.

Real quick, there is a slightly increased risk of having AML/MDS with patients who are receiving PARP inhibitors. Oftentimes the provider is talking to the patient about this when they’re recommending the PARP inhibitors. But the patients are going to ask you about it, and so you need to be aware that there is an increased risk. And this is also something that you want to consider when considering how long you’re going to keep them on PARP inhibitors, being aware of this risk factor.

Both olaparib and niraparib come in tablet form now. The recommended starting dose for olaparib is 300 mg twice a day. If a patient has moderate renal impairment or they’re on a strong CYP3A inhibitor you start them at a lower dose level. For olaparib you just monitor their CBC once a month — or check it at baseline and then once a month. For niraparib the starting dose is 300 mg. The next slide kind of goes over the individualized dosing for niraparib, but if their weight is less than 77 kg or their platelets are less than 150,000, you start them at a lower dose level. Niraparib gets weekly CBCs for the first month, and you also want to monitor their blood pressure. And again, that’s where those video visits come in handy, checking their labs, checking their blood pressure.

This is just a quick slide that goes over the starting at 200 mg daily for the patients who have a weight of less than 77 kg, or 170 pounds, or if their platelets are less than 150. If their weight’s above that or their platelets are above 150, then you start them at 300 mg.

And then dose modification. I think this is really important for nurses to be aware. A lot of our patients on PARP inhibitors have to hold treatment or have to be dose reduced at some point, and telling your patients this early on makes them a lot more likely to be open to the idea of dose reducing or holding treatment. We have a lot of patients who are nervous about holding treatment, especially once they see that it’s working, or decreasing the dose. And if you tell them ahead of time there’s a really good chance at some point we might have to hold treatment or decrease the dose, they seem to be a little bit more open to the idea. So as nurses make sure you’re talking to your patients about this.

DR LOVE: So Jennifer, again, that’s a theme we’ve already talked about several times here at ONS, the potential for dose reduction, particularly for these longer-term oral-type therapies. And we’ve talked about — Courtney just mentioned sometimes patients get very nervous about the dose being reduced. Can you talk a little bit about how you think about it and how effective it is in ameliorating symptoms by reducing the dose?

MS FILIPI: Yeah. First of all, very good point to bring that up early and let your patients know that this probably will happen. It’s very common that we’re dose reducing or holding the PARP inhibitors. And oftentimes just a dose hold, maybe a week or so, does wonders for the symptoms. If it’s a 1-time anemia issue, and we transfuse them, sometimes we can put them back on the same dose. Other times we might want to dose reduce at that point.

But another point to bring up is the lower doses are still efficacious, so I always make sure to tell patients that as well.

DR LOVE: So Shannon, again, I can remember when the breast and prostate people saw the AML/MDS incidence in ovarian they got very, very nervous. You saw 4% versus 8%, but also notice this is in recurrent disease, because chemotherapy increases the risk, and these patients have had a lot of chemotherapy. And it seemed, and we saw this in breast and prostate, too, that once you brought it in earlier they had less chemo, much lower risk. Right now for a patient such as the one we just discussed, that Courtney and Dave have, what do you say to a patient if they say tell me exactly what my risk is?

DR WESTIN: Yeah. I mean, I tell them basically it’s around 1%, probably, based on the data. And again, like Dave said, we want to give our best drugs as early as possible because we want them to work as well, but it’s also the case of it may be safer, too, to give our best drugs as early as possible in this setting. And as you mentioned, when we give it in the recurrent setting it can still be safe, but we used to just continue the PARP inhibitor forever in the recurrent setting, and that’s probably not safe. So I think having a nice duration of therapy that we know we can give it for 2 or 3 years, and we have the lowest chance of developing something that could end up being a tragedy, it makes us feel stronger and more confident when we counsel these patients.

DR LOVE: So Dave, maybe you can summarize a very complicated story in terms of the use of PARP inhibitors in the recurrent disease setting and the fact that the FDA looked at some of these numbers that we just showed and actually pulled back the indication for using PARP inhibitor in recurrent disease. And yet this came out at SGO, there are situations, you might have a patient like your patient, she could end up recurring, and would repeating PARP in a patient like that, who had a prior PARP, be a consideration? Are there situations right now where you can or do use a PARP inhibitor in the recurrent disease setting?

DR O'MALLEY: So the OReO trial was done in Europe, and it looked at PARP after PARP, and that did show a difference in those patients. Diving down in that data the only person I would consider PARP after PARP is if they’re on clinical trial or they did not progress on a PARP previously. If our patient recurs 3 years after starting a PARP I absolutely would consider bringing a PARP back in maintenance therapy down in the future. But if she would have progressed while on PARP, outside of a clinical trial, where we have trials that are trying to overcome PARP resistance, I’m not going to do it.

Now, we hope with the education of all of us that everybody gets germline and somatic testing, and we identify patients who are going to benefit the most from this therapy, BRCA patients, and those are now the only indications in the US which persist in the recurrent setting, BRCA patients. But we don’t ever want to use that. We all want to use it up front. So make sure we get tested, alright?

DR LOVE: So we’re going to move on in a second and talk about other strategies being used in ovarian cancer. Again, we did an entire program on HER2-positive ovarian cancer a couple years ago. I never could have imagined that, but now we have an antibody-drug conjugate that’s actually approved for any cancer where you have a positive HER2 assay. And now after all this experience in breast cancer we’re following these other disciplines, including gynecologic oncology, now using this agent. Really an interesting development, because again, the general oncologists have already used it in breast cancer, but we get into GI cancers, we’re going to talk about Saturday afternoon, we use HER2 therapy there.

Other Available and Investigational Novel Strategies for OC

DR LOVE: So Dave, let’s talk a little bit about some of the new developments. This is a case where a patient gets PARP inhibitor maintenance but then has later on disease progression. Remember, not everybody is cured here. They get a couple more cycles or treatments with chemotherapy, now they’re resistant to platinum, but found to be HER2-positive. And I would just say in any patient with recurrent ovarian cancer, a really good idea to take a look at the chart and make sure they have a HER2 test in there, because, as you’ll see, an effective treatment option available. So Dave?

DR O'MALLEY: HER2 and folate receptor, every single patient. So let’s talk about that. And I think when we look here we’re learning a tone from the breast cancer. We’re teaching them about PARPs. They’re teaching us about T-DXd.

So what is an antibody-drug conjugate? We have a drug which connects to a protein on the cancer cell, differentially expressed versus normal cells, so HER2 is not expressed on normal cells, it’s expressed on the cancer cells. It connects. It’s linked to a cytotoxic payload, a chemotherapy. That chemotherapy T-DXd, because again, for me to say trastuzumab deruxtecan gets a little tough, so I’m going to call it T-DXd, okay? Still a generic name, okay? Alright?

So it has a cytotoxic payload, a TOPO1 inhibitor drug. So I think when we’re looking at this, making sure we know what the payload is is essential, and what the target is. I used to think linkers were a bunch of crud, but with the new technology the linker’s important, too, but that’s for a different day. Maybe a couple of years from now at ONS.

Alright. So why did Neil just say test everybody, okay? Because the expression seen across tumor types and the recent FDA approval is in 3+, using gastric scoring, were not going to get into that, 3+ HER2-positivity. So on this graph, beautiful paper looking across disease sites, you see the difference between those that had any expression versus those with 1+, 2+ and 3+.

So on the left schematically, on the right in a table form, whatever your preference is. But when we look across there endometrial is high, ovary is modest, and we have about a third of the patients who are going to be positive. But what is positive? And that’s what was funny about that case. I don’t know what positive is, but we definitely know that 3+ is a positive.

So in the same paper they looked at the breast cancer literature, because I get asked this all the time, when should I test. We usually say the most recent biopsy. We also say should we send the primary tumor or the metastatic? We don’t know. I wish we could send both, but there’s some challenges.

So this trial looked at primary versus metastatic. And if you look at the bottom, in those greens, the HER2, there’s not much difference between the primary versus metastatic. When you have a HER2-low you’ll see some migration in HER2-negative on the metastatic. And then when we look at the cross time first, second and third biopsies again you see some migration. So in general I’d send the most recent tissue, but I have to admit if I send the primary, and it’s negative, I will send the metastatic because that’s really what is dictating care in the recurrent setting.

And what we’re alluding to. This landmark paper, and it’s called pan tumor — DESTINY-PanTumor02, and it went across solid tumors, and you see here the expression. When you look at this graph you have to be careful because on the far left of each of the triplets are all the patients, the middle is 3+, and the next is 2+. But as my seventh grader taught me, using a little algebra, that the alls, which means the 0 and 1+, looked pretty similar to 2+. We’re going to talk about that in Gyn.

So the FDA said look at how good 3+ is. We’re going to give you an agnostic indication for 3+. And this was the data I was waiting for, presented by Dr Lee last year’s IGCS. And we see here, this is centralized testing, for the patients to go on the trial they had to have local testing of 2+ or higher. But when they tested it essentially they found that some of those that were called 2+ locally were called 1 or 0. And you see that. We see activity across even 0.

Am I advocating to give T-DXd in 0? No, I’m not. I’m advocating we need to figure out a better test, and we need to identify those patients who are going to benefit more. But we see activity across the Gyn tumors at all levels of expression.

So we’re taking that data, and we’re designing a Phase III. Joyce Liu, from Boston, is the lead of this trial in ovarian cancer. And they are allowing ovarian cancer 1 to 3+ for patients in the first-line setting who are not a candidate for a PARP inhibitor. I would argue that’s HRD test negative, but that can be interpreted.

But there are other ADCs. R-DXd we saw, Katie Moore presented this data last year, and we see, again, a similar payload, the deruxtecan is referring to the topoisomerase payload, but this is against CDH6, another target. That’s a pretty amazing waterfall plot. Everybody got disease regression except for 2 patients, and the overall response rate we use with the … activity, which is what we report, is 49%.

That led to the design of another Phase III trial, which is ongoing right now. First we have to figure out the dose. That’s called dose optimization, that’s what the Phase II is, and that enrolling now, okay? That’s what I can say publicly. And once we figure out the dose, then we’re going to compare it to the standard of care arm, okay, standard of care chemo, excuse me, and they’re listed there, gemcitabine, PLD, topotecan or paclitaxel.

So we are going to start in a similar — in that case it was recurrent ovarian platinum-resistant cancers were testing in the early stages, and now at the same time we’re testing the recurrent setting. So we’re trying to bring … earlier, bring those best therapies earlier on in treatment. Clearly we have an active agent, T-DXd, antibody-drug conjugate. It is the era of antibody-drug conjugate. A lot of the work Shannon and I are doing is the post-ADC world, okay? We need to figure out the testing, and we need to get patients enrolled on clinical trials.

Yeah. I’m already at time, Neil, but this is an amazing case in a patient who was on a clinical trial, line of therapy was the third. She was on a clinical trial. We treated her with a checkpoint for 5 years. At that time we found out she was mismatch repair deficient. She had some challenges in that clinical trial, from actually financial, and said I will not go on a clinical trial again.

So she came in, we tested her, she was HER2-positive. She continues to get treated. You see that big gumba, that circle. That was a symptomatic abdominal wall recurrence. And you see here she’s in ongoing partial response, and we just treated her with her actually twenty-first cycle. I think that was last week, right, Court?

MS ARN: Couple weeks ago, yeah.

DR O'MALLEY: So pretty amazing we’re seeing this type of response.

DR LOVE: So pretty amazing being in medical oncology nowadays. I was just flashing on the fact we did an entire hour program recently on HER2-positive biliary tract cancer. That was one of those tumors there. Also the fact that we talked on Wednesday night about how effective T-DXd in breast cancer is in so-called “HER2-low,” 1+ or 2+. We don’t really have a lot of data outside of breast cancer yet to know if it’s going to be effective, if it's going to be approved. It’s approved in breast cancer, even ultralow, which is almost none there, you still see very good responses.

So Shannon, a question from the audience. There’s another kind of thematic issue in oncology we’ve been talking about all week is that often there are multiple agents in the same type of drug. I want to go back to PARP because we got a question from the audience about choosing between niraparib and olaparib. And you have to compare the olaparib data to the niraparib indirectly because they weren’t compared directly. I’m curious how you think it through. From your point of view, Shannon, are they equally effective in BRCA patients? And if so, how do you decide which one?

DR WESTIN: Yeah. I mean there’s definitely a class effect, right? So if we’ve got the target, that drug that hits that target or takes advantage of that target should work, right, if it does its job. And all of the clinical data would indicate that niraparib, that olaparib, that rucaparib, they do their jobs. So then we’ve got to use some different nuances. We look at the FDA indication, right, what are we likely going to get an approval for. And my colleagues have referenced this. We want to make sure that the patient can afford the drug, right?

So we also look at things like side effects and pre-existing toxicities. And so certainly niraparib, for example, it can cause hypertension. So if I’ve got a patient that already has pre-existing hypertension perhaps I look towards olaparib. Conversely, niraparib doesn’t have as much interaction with different drugs, drug/drug interactions, and so if I have a patient that already has polypharmacy I might lean towards niraparib because I know that her drug’s not going to interact with all the drugs she’s already on.

DR LOVE: You mentioned, or Dave mentioned, the only PARP approved without BRCA, the wild-type patients, is niraparib. What are the situations where you would use niraparib in a patient who doesn’t have a BRCA mutation or an LOH positivity?

DR WESTIN: Yeah. I mean, I think — I think Dave and I have both already referenced this. I feel really uncomfortable not giving some kind of maintenance therapy to a patient with advanced ovarian cancer because I know her chance of recurrence is so high. So if I haven’t started bevacizumab, or if that was something that was perhaps contraindicated for her at the beginning, then I’ll talk to her about the existing data for niraparib.

And it really then comes down to shared decision-making, right? We all have those patients that want to do something no matter what that something is, and they’ll take any risk, or they’ll take any adverse toxicity. And then we also have patients that have that idea of I would just like to be done for a little while and come what may. I’ll take that if I can have 3 months off. And so I think really that’s where shared decision-making comes in, around yes, this is what the potential benefit is, let’s weigh those risks and benefits for you.

DR LOVE: Jennifer, from a patient education point of view, what are some of the things you think about with a patient who’s going to start niraparib versus olaparib? Or is it pretty much similar?

MS FILIPI: They are very similar. With niraparib it’s a little bit harder on the bone marrow, so if you — especially if you have someone that had some trouble getting through up-front chemo with some thrombocytopenia or neutropenia, anemia, the recommendation is to actually monitor weekly for a month, the CBC weekly for a month, where olaparib, some physicians and NPs will do weekly and some will just go right to monthly. So that’s a little bit different. And then with niraparib, as Shannon mentioned, it can cause hypertension. So there are class effects, but they also have their unique things, right? So olaparib, there’s a risk of pneumonitis of all things, so just knowing those unique side effects and knowing your patient as well.

DR LOVE: Again, you’re trying to compare indirectly. I hear more about anemia with olaparib, thrombocytopenia. Courtney, I think, may have alluded to the dosing of niraparib, the “weights and plates.” How does that play out in practice?

MS ARN: Yeah. We’ve definitely seen benefit. Initially we were starting everyone at the same dose level of 300 mg daily, and we were having to significantly dose reduce a lot of our patients or stop therapy because of severe thrombocytopenia. And so since doing the weights and plates and dosing — doing the individualized dosing our patients seem to tolerate it a lot better, and their hematologic toxicities improved too.

DR LOVE: Actually, Shannon, I was just flashing on another mini video I did of you from the SGO Meeting talking about the question that always comes up in any cancer, what about immune checkpoint inhibitors.

DR WESTIN: Yes.

DR LOVE: And there have been a lot of studies looking at that. And it was interesting because there are a couple of studies looking at I think olaparib as well, but nothing really convincing, and the bottom line was I heard you say we’re waiting for the “FIRST” trial. What’s the FIRST trial?

DR WESTIN: Yeah. So yes, to your point. Well, maybe next time you should just have me on camera, have a video of me, you don’t have to pay for me to come here.

No. The bottom line is can we add immune checkpoint to the pre-existing PARP inhibitors, to bevacizumab, and the first trial is potentially going to answer that. So the patient with advanced ovarian cancer get chemotherapy, bevacizumab and a PARP with or without immune checkpoint inhibitor dostarlimab. And so that’s going to tease out the question of the addition of immune checkpoint to PARP and bev.

DR LOVE: It’s starting to sound like multiple myeloma, 5 drugs.

DR WESTIN: Yes.

DR LOVE: Really interesting, but if it works. Again, in myeloma they use 4 drugs all the time to start therapy. And now this is with niraparib. There were other studies. You were mentioning there are 2 — that the way the study was designed — the other studies weren’t “designed” exactly to answer the question, but this one — if this turns out to be positive are you going to use niraparib or you would use any PARP inhibitor?

DR WESTIN: That’s a great question. I think we’re going to have to see how positive. We’re going to see what the data look like, right? I’m hedging a little bit, forgive me. But I think you would start where the data are the strongest, and so if it is positive, then you’d be looking at using niraparib and dostarlimab. But with that being said, some of the other studies that have looked at this, for example DUO-O, that study was not — was written more like a PARP inhibitor trial. We didn’t get to answer the question of what the addition to the — of the checkpoint really did. It was missing arms. We have a bunch of trials with missing arms.

And so when they came back positive we were left with the question, well, what would have happened if we just gave PARP here. So I’m hoping FIRST will be a little bit more definitive and really will help us, because everyone, all the patients want — they want immunotherapy, right? It’s on all the commercials. They’re like is this drug right for you? And they’re like is it? I want that. So yes. So I’m hopeful. For now we’ve been hedging, no, no, but maybe we’ll get some more data.

DR LOVE: Yeah. Well, immunotherapy’s gotten into the Super Bowl commercials.

DR WESTIN: That’s right. That’s what I’m talking about.

DR LOVE: So people are very aware of it. And also it gets into another theme in oncology, again, when you have multiple agents in the same class. This came up, actually, in lung cancer we were talking about this, where all the positive trials are with pembrolizumab in advanced metastatic disease, but then the only positive trial in the locally advanced disease was for another IO, durvalumab. But even though everybody thought IOs are all the same that’s the one they use because you stick with what’s in the trial. So we’ll see what happens with this FIRST trial.

And also you made a great comment, too, that these studies, when they’re designed, we don’t know what’s going to be — by the time they’re mature 3 or 4 years later things are different, and so it’s hard to pick the exact way to do it. But I hope, I don’t know, we’re going to see the results from this study soon.

Okay, well let’s go on. We were talking about T-DXd. I diverted out there because I’m getting a lot of questions here about PARP. But Courtney, let’s talk about the nursing considerations with T-DXd.

MS ARN: Sure. Just like the PARP inhibitors, patient education is really important, so you want to talk to them about what T-DXd is and why they’re receiving it. You also want to talk to them about potential side effects and what to expect, as well as symptom management. You also want to talk to them about pre and post medications. We’ve definitely found that implementing premeds and home meds has significantly improved the side effect profile. And then baseline labs and procedures. Patients receiving T-DXd do require baseline echo.

Dr O’Malley talked about T-DXd and how it works. When I’m telling my patients how it works, again, I try to simplify it as much as possible. I tell that there’s 3 parts. There’s this monoclonal antibody, and then there’s the payload, which I tell them is like the chemotherapy, and then a linker that connects the 2. And how does that work to treat their cancer? Essentially this monoclonal antibody targets the HER2, which we know that they’re positive because they’re getting T-DXd, and then it’s linked to the chemotherapy, and the chemotherapy releases within the cells causing cell death. And explaining it to them that way kind of helps the patients understand why they’re getting it. And I’ll also use it as an opportunity to talk to them about their HER2 results and why we’re recommending T-DXd.

The most common side effects with T-DXd are nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, diarrhea, musculoskeletal pain and hematologic. The most common hematologic we’re seeing is anemia and neutropenia. We also see thrombocytopenia, increase in LFTs, as well as hypokalemia.

There’s also a risk of ILD or pneumonitis associated with T-DXd. So 15% of patients receiving T-DXd did have pneumonitis. 87% of those patients had their first event within the first year. The median time to onset was about 5 to 6 months. So this is something really important to talk to your patients about.

There’s the 5 “S” strategies that helps, but essentially prior to starting treatment with T-DXd you want to make sure you’re talking to them about the risk of ILD, and you want to tell them signs and symptoms that they need to report. Every time they come into clinic you want to ask them if they’re having cough, shortness of breath, fevers. You also want to look at their vital signs and make sure that they haven’t had a drop in their oxygen level. We’ve certainly had patients come in who are not having any symptoms, but their oxygen level’s much lower than their baseline. When we get imaging we find that they do have pneumonitis. So talk to your patients about symptoms to be looking for but also make sure you’re assessing them at every visit.

The 5 S strategies; screen. So be careful what patients you’re considering for T-DXd if they’re at high risk of pneumonitis. Get the baseline imaging to make sure they don’t have any pre-existing lung disorder that would increase the risk of pneumonitis. And then the synergy means work as a team. So make sure everyone in the office, the nurses, nurse practitioners, physicians, patients, everyone is aware of this risk of ILD or pneumonitis, and everyone’s on board looking for any signs or symptoms indicative of pneumonitis. If there’s any suspicion for T-DXd you want to suspend or hold treatment until proven otherwise. If ILD or pneumonitis is confirmed then you want to treat them with steroids. So screen, scan, synergy, suspend, steroids.

Again, monitor all of your symptoms — your patients for symptoms, talk to them about signs and symptoms to be looking for, at every visit make sure you’re assessing them.

If ILD is suspected you want to hold treatment, you want to work them up for ILD. If they have Grade 1 pneumonitis, which is asymptomatic, you hold T-DXd until it resolves and then restart them at the same dose level. If it takes more than 28 days for their pneumonitis to resolve then you would restart them at the next lower dose level. You can consider steroids for a Grade 1 pneumonitis, but they don’t have to be given. But you do need to hold T-DXd until it resolves.

Per the package insert, if a patient has Grade 2 or higher pneumonitis then you permanently discontinue T-DXd, and at this point you would give them steroids.

This just kind of goes over the management of the most common AEs that we’re seeing with T-DXd. First, for the anemia, neutropenia, thrombocytopenia sometimes you need to transfuse, sometimes just holding, their hematologic toxicities improve. A lot of our patients are requiring growth factors, so keep these in mind. If you’re having patients with neutropenia, thrombocytopenia, anemia make sure you’re adding the growth factor if indicated, holding, dose reducing or transfusing as needed.

When we first started using T-DXd we were seeing a lot of nausea on the Phase I clinical trial. Now that we’ve implemented premedications and home medications with antiemetics for our patients our patients really aren’t having that much nausea. So make sure you’re using premeds in the IV prior to giving T-DXd but also sending them home with 3 to 4 days of home antiemetic regimen to help prevent nausea. With doing this it significantly decreased the risk of nausea/vomiting.

Fatigue is very common. Make sure you’re assessing patients for fatigue at every visit. Consider holding/dose reducing depending on how severe it is. You also want to rule out other causes. And again, consider physical therapy. We’ve seen a lot of benefit in our patients receiving physical therapy while undergoing cancer treatment.

Because it can cause left ventricular dysfunction patients do need to get a baseline echo and then every 3 to 4 months while on treatment.

If a patient develops diarrhea you first want to rule out any infectious cause. Once that’s been ruled out you want to start them on an antidiarrheal. Unlike PARP inhibitors, this is an every 3-week regimen, so it’s not something that they have to be on every single day, but some of our patients do require scheduled antidiarrheals. It seems to kick in about 5 to 7 days after their dose, so just because they don’t have it the first few days doesn’t mean that they won’t develop diarrhea. All of your patients starting T-DXd should have an antidiarrheal available at home in case they do develop diarrhea. Talk to them about when to take it but also make sure they’re calling if they develop diarrhea.

T-DXd can also cause alopecia, so make sure you warn your patients that they might lose their hair, order them a wig if needed, and then some of our patients are electing to do the scalp cooling.

T-DXd is given IV infusion once every 3 weeks. The initial infusion is given over 90 minutes. If the patient tolerates it without any infusion-related reaction all subsequent infusions are given over 30 minutes.

It is important, real quick, that T-DXd is given until disease progression or unacceptable toxicity, so make sure all of your patients are aware that they will continue receiving T-DXd as long as it’s working and as long as they’re tolerating it. So it’s not like some of the prior chemotherapies where maybe they got 6 cycles and then moved to a maintenance setting. They will continue getting T-DXd as long as they’re tolerating it and as long as it’s working.

The recommended starting dose for T-DXd is 5.4 mg/kg. If they require a dose reduction, the first dose reduction is 4.4 mg/kg, and the second and final dose reduction is 3.2 mg/kg. But I really can’t emphasize enough how much supportive care helps, so hold treatment, use your supportive care, mitigation strategies, before jumping to dose reduction if you think it’s safe.

Infusion-related reactions are rare, but it did happen in 1 to 3% of the patients, so be on alert for this. If a patient has a Grade 1 infusion-related reaction reduce the infusion rate to 50%. If it’s Grade 2 you temporarily stop the infusion. Grade 3 you permanently stop.

Quick case study just to end the T-DXd. So this patient had recurrent high-grade serous ovarian cancer. Her IHC was notable for HER2 3+, and she was folate receptor 0+. She was initially diagnosed in 2020. She completed adjuvant carboplatin and paclitaxel followed by PARP maintenance. She then recurred in 2023 and was treated with gem/cis/bev followed by bev maintenance for 9 months. Once she progressed she was retreated with gem/cis/bev, progressed after 3 cycles of maintenance bev, and then she became platinum resistant, and at that point, because of a HER2 3+, she was started on T-DXd.

After 3 cycles of T-DXd she had a near-complete response. She tolerated treatment well, with the expected side effects. She had fatigue, some diarrhea, but with supportive care we did not have to dose reduce or hold her treatment. We just used the supportive care measures. She’s maintained the same dose every 3 weeks.

She really enjoys traveling, and she’s been able to continue to do that while staying on treatment with T-DXd, and she’s overall tolerating it really well. We’ll repeat imaging after 6 cycles, but right now she had a nice response after the first 3 cycles.

DR LOVE: How is she feeling? Did she have tumor-related symptoms before she was on T-DXd?

MS ARN: She did. She had abdominal pain, early satiety, and both of those improved after the first infusion, within a few days of the first infusion.

DR LOVE: I was mentioning how the pandemic affected our ability to present cases. We’ve now been — and we did this at SGO in the HER2 meeting, we do these little mini videos of docs in practice presenting cases. And so we had this planned that we were going to present a case of HER2-positive gynecologic cancer, and I’m like I don’t know if they’ve got any of those. It just was recently approved. And it was amazing to talk to these docs because everybody had cases like this one. And it kind of reminded me about 3 or 4 years ago the smile that came on their face when they were presenting. I remember one of the docs it was the first time she used T-DXd, and the patient had this great response. And I remember the docs 3 or 4 years ago in breast cancer going wow, this thing works.

But Jennifer, the other issue is the tolerability issues. Can you comment a little bit more about GI issues, chemo-like side effects? And one thing I’ve heard from the breast people, I’m curious what your experience has been, is the value of olanzapine in these people.

MS FILIPI: Yeah. Good questions and comment. While Courtney was talking I was thinking of actually our first experiences with T-DXd, and I was kind of caught off guard, to be honest, with how toxic it can be. But once we kind of got the hang of it and put on the right antiemetics and got kind of a standard schedule down it went much better. And we actually, I wanted to mention, have a patient with platinum-refractory disease who is now a year on T-DXd with a partial response ongoing and is feeling great, so it is definitely an active drug.

In terms of GI side effects, we will do steroids prior to treatment, as well as something like ondansetron. And then that night we’ll start olanzapine, and we’ll do either 2.5 or 5 mg based on — based on the patient’s comorbidities, how old they are, that sort of thing, and then we’ll continue that for 5 nights, actually. And then for steroids we’ll continue those for 2 or 3 days, depending on how they do. And that’s something we can even taper out a little bit if someone has a really hard time.

And then I think Courtney mentioned diarrhea, too, which can be a huge issue for this drug, so much so that we’ve had people come in a week later each cycle for some electrolytes, IV infusions. But I think this is where nursing comes into play so much because it’s all about the education, the early recognition, the relationship with the patient, saying you call me no matter what, no matter when, we’ll figure it out.

DR LOVE: So another word in terms of T-DXd, Shannon, in terms of ILD. Again, it was interesting when this pan tumor approval came out, and we started to hear from the GU docs and the GI docs, and they had heard about ILD, and they were saying we need to watch for symptoms, and we’re like no, you’ve got to get it before it’s symptomatic. You want to get them Grade 1 without symptoms, just imaging. The breast people image these patients every 6 to 9 weeks trying to find the earliest changes. Is that the strategy you use, Shannon?

DR WESTIN: 100%. We are real twitchy about ILD because we’ve had some patients get real sick real fast. And so you really — you cannot sleep on it. So you keep your imaging, and it can’t just be a chest x-ray. It has to be a CT scan. And the minute you see anything, even if you think oh, that patient was sick, and probably this is just inflammation, you can’t make those kind of assumptions because once you get past Grade 1 you don’t get to use that drug anymore.

And the recommendations are that if it’s just Grade 1, and it resolves, you can restart at the same dose. We’ve been considering reduction quite a bit because we don’t want to accidentally get a patient right to Grade 2 and then lose the opportunity they get this really, really active drug.

DR LOVE: Yeah. We hear cases all the time in breast cancer of people who get picked up as Grade 1, they get it restarted, they continue with a response, so really critical.

Alright, Jennifer, let’s talk about some other nursing issues in ovarian cancer.

MS FILIPI: Great. Alright. I’m excited to present this case. She’s, I know we shouldn’t say this, but one of my favorites. We’ve been talking a lot about clinical trials, and we’ll get into it in a little bit, but how you present clinical trials and when you present clinical trials to our patients is so important.

So this patient is a young, 39-year-old. She’s a therapist, an artist, an avid traveler, and she now has platinum-resistant ovarian cancer. She had negative genetics, folate 1 receptor negative, HER2-negative, so she didn’t have a lot of options. So we did present a clinical trial to her, and she went on it. She’s had a great response.

You can’t really see that list, but that’s her to-do list of local places around New England she wants to visit. And the troll is the troll from the botanical gardens in Maine. It’s a picture of her with her family doing a ziplining thing. So this has all been done when she’s on clinical trial, which is so amazing.

So you get a couple different groups of people when you’re presenting a clinical trial to patients. The first group is people that are kind of like whatever you say. I want to beat this. I don’t care the cost, the toxicity, whatever you’re recommending I want to do. Then you have that middle group that’s kind of like I’m not sure, I want some more information. You can usually explain in detail what’s going on, and they’ll kind of make a shared decision.

And then you have a group that feels very uncomfortable with clinical trials. Maybe they had a family member with a bad experience or just things that they’ve heard in the media or lifelong just negative effects that they’ve heard of clinical trials. So that’s really the group we want to kind of concentrate on and spend as much time on as we can. I always want to bring up there are some advantages, as we’ve seen presented here today. Here’s a good potential you’re going to get an active drug. We’ve had a lot of FDA approvals in the last 5 or 10 years. You’ll have your own clinical trial team with a clinical trial nurse and a clinical coordinator that coordinates all of your visits. And you’ll keep your same team, so I will be there, your doctor will still be there, your nurses will still be there. And then a lot of people often say that they feel good about contributing to ovarian cancer research or contributing to the fight.

There are a lot of barriers, though, with clinical trials. Especially at first the visits can be very frequent, as we know. So especially in Boston, where there’s a ton of traffic, people could be coming 2 to 3 hours multiple times a week, and that’s a lot of time, that’s money. And oftentimes, actually at all of our sites locally, there aren’t clinical trials available yet. Hopefully that’s coming in the pipeline, but that’s another barrier. Eligibility requirements. They’re often very strict. So it’s really important that we’re presenting clinical trials at each phase of the cancer trajectory, meaning at each progression of disease, because the longer you wait sometimes they have a 2- or 3-line limit.

And then just to communicate with the patients. I touched on this a little bit. But a lot of people have this negative connotation, I don’t want to be a guinea pig. I don’t want a placebo. But then you explain there are no placebos on this trial, and they think about it a little bit differently.

And then I always want to stress that no matter what the patient decides we are your team. You’re not going to be treated differently if you don’t do this, because I think sometimes people feel a little bit of pressure.

And then sometimes the pharmaceutical companies will give vouchers and help pay for hotel stays, so that’s something to keep in mind as well.

So a good time to kind of talk about optimizing this oncology nursing care. It’s a good time to check in at each progression what are your goals. How has this changed since your first diagnosis? It’s good to introduce palliative care. And these are hard conversations, right? They’re not conversations that are going to happen in 1 visit. But just kind of establishing and keeping that nursing relationship with the patients is so important.

Of course, we’ll want to, like Courtney has talked a lot about, educating the patients on not only their disease, what does it mean that I’m Stage III or Stage IV, but the management of different side effects of whatever trial they’re on or whatever chemotherapy regimen they’re on. We have all sorts of support, resources, social work. Lifestyle medicine is kind of an up and coming thing that can help optimize patients’ health outside of their oncology care. And then of course you want to be mindful of social/financial barriers, and I love the motto “never worry alone.” This is, again, where the nurse/patient relationship comes in so much, and that’s what I tell all my patients. If you’re worried about something it’s never too small. You wouldn’t believe the messages I get. Just reach out.

And then I think we already touched on the multidisciplinary approach, and I am running out of time here.

So back to our case. She’s just a truly amazing patient. We’re so happy for her. She’s been in a partial response, symptom free for over a year now on this clinical trial. She’s really given back and is involved in Turning the Tide, which is an ovarian cancer retreat up in New England, and she is now teaching tai chi classes to other cancer patients.

DR LOVE: So a really good thought to keep in mind. This is a potential benefit to the patient. It wasn’t that long ago, when you look at some of these trials comparing chemotherapy A to chemotherapy B, either one you could get in the community, now you see agents you can’t get, like this patient. Think about the patients who went on that SOLO-1 trial, the people who got the olaparib are on that curve. And then your patient, she got started in 2020. It was presented in 2018. So there’s a benefit to the patients participating as well.

Current and Future Role of Mirvetuximab Soravtansine in OC Treatment

DR LOVE: Let’s talk about — it seems like every time we do a program, regardless of tumor type, the issue of antibody-drug conjugates comes up. Again, I refer you to our program Wednesday. We spent an hour and half about ADCs.

But in ovarian cancer we have mirvetuximab. Let’s talk a little bit. And here we have a biomarker, again, that we’re looking for, folate receptor alpha. We’ll talk about the considerations in starting a patient on this. But Shannon, can you talk about what we know from the clinical research about this agent?

DR WESTIN: Yeah, absolutely. I’m excited to talk about mirvetuximab soravtansine. I don’t know why you have such a hard time. In solidarity to Dave I’m going to call it mirv.

DR LOVE: Mirv.

DR WESTIN: So we’ve seen the typical course of ovarian cancer, and a lot of us have been mentioning platinum resistant/platinum sensitive, and this is just meant as a little bit of a reminder, right? So if we have a patient whose tumor comes back more than 6 months after the completion of platinum they’re technically platinum sensitive, and for them we can consider platinum again. It’s the patient population that has recurrence of disease prior to this marker, within 3 months, within 4 months, or even platinum refractory, when they have a recurrence during platinum, that’s where we have a really huge area of unmet need.

And we used to say, at least I used to say to patients when they presented with platinum-resistant disease, this is an incurable disease. But now we have data, like we just saw with T-DXd, and also with mirv, that there are patients that potentially can be cured.

So mirv targets folate receptor alpha, and as Dave told you, when you use these ADCs you want a target that’s not necessarily expressed on normal cells, and these are very highly expressed in ovarian cancer, as well as some other cancers, and especially in epithelial ovarian cancer and high-grade serous, which is arguably one of our worst actors, there is a high proportion of patients that will have expression. Now, this is all expression, and any expression is not necessarily associated with benefit to mirv, so we’ll talk a little bit about what that means.

Right now the say we test for expression, this is something you can get — your institution might do it, or you may have to do a send out. There are a number of labs that will do this. We use the so-called PS2 scoring, which is determined based on how strongly the cells stain and the proportion of cells that stain, and we get a 1, 0, 2+ or what have you. We’re looking for 75% expression based on the current use of mirv.

So this is an antibody-drug conjugate. You heard a master class on how those work, so I won’t go into that in detail. This is a DM4 payload, so a little bit different from some of the other payloads that you’ve seen. And that matters because if we are potentially going to sequence these, if we have a patient with HER2 positivity, and a patient with folate receptor alpha, we can do that. We can argue about which one we would give first, but if there’s ultimately the patient can’t tolerate, or there’s progression of disease, we can use both of these because the payloads are different.

The initial approval for mirvetuximab was in platinum-resistant ovarian cancer based on the so-called SORAYA trial, which was a single-arm trial, and we saw beautiful response to therapy. So we got an FDA approval solely based on the fact that 31% of patients had reduction in their tumor, and it lasted about 7 months, which that was nothing to sneeze at.

And so we went on, as we do with the FDA, to prove this in a larger group of patients, and that was the MIRASOL trial. And this was led by Dr Katie Moore, where patients, again, platinum-resistant ovarian cancer, folate receptor alpha expression greater than 75% based on that PS2, and 1 to 3 prior lines of therapy were randomized to mirv or to investigator’s choice chemo. And hey, pro tip, if there’s more than 1 investigator’s choice chemo, that means none of them are that great, right, and so you can always look at a trial and understand how great is the standard of care, not great.

So we looked at progression-free survival in this population, and not only did we see progression-free survival benefit, we also got overall survival benefit. This was the first study ever in platinum-resistant ovarian cancer to demonstrate an overall survival benefit, so this was really exciting. And of course at the bottom you can see the waterfall plots, right? There’s a nice shrinkage of disease. So even though we had a 30% response, you can see a large proportion of patients had some kind of reduction in their disease, which would be expected to provide symptomatic benefit as well.

Now, so as you’ve learned, right, if we like something in a later line of therapy let’s move it up as soon as we can. So there are a couple of trials that are looking at this drug or have looked at this drug in platinum-sensitive disease. The first is the PICCOLO study, which looked at mirv as a single agent in platinum-sensitive ovarian cancer, with a response rate of 51%, so pretty exciting. Shockingly, we don’t really know the response rate of carboplatin here, so I can’t say if this is better or worse. It’s certainly in line with what we’d expect with platinum-based therapy, so this could be an option for patients that test positive for folate in lieu of platinum, if they maybe can’t tolerate platinum or have a prior sensitization — or a prior reaction. And the duration of response is beautiful, about 8 months.

And they did do some teasing out, and it seemed to be active in patients that have had prior PARP, prior bevacizumab, so that’s important, understanding, again, sequencing, that this drug may be very effective.

And then finally we have the GLORIOSA trial, which is ongoing right now, that is looking to see can we add mirv to our standard of care maintenance. And so in this trial patients have platinum-sensitive disease, they’ve responded to their platinum, they have folate receptor alpha-positive testing, and they’re randomized to either continuing bev that’s been started with their chemo or adding mirv to bev. And so we’ll see if we can change the standard of care for maintenance in this space.

DR O'MALLEY: And did you say that’s the best trial ever?

DR WESTIN: Oh. This is David’s trial. Excellent trial. We’re so proud of him.

DR LOVE: So quick question. This came up at SGO, Dave. Now we have 2 antibody-drug conjugates in ovarian cancer. We talked about T-DXd and mirvetuximab, both with biomarkers. There are some patients who have both. If that’s the case, which one comes first, Dave?

DR O'MALLEY: You have to go with the overall survival benefit right now. If you had 3+ and a high folate receptor alpha, that’s pretty rare. But you have to go with the one that’s shown overall survival benefit, in my mind. You can say if you had a clinical trial where you could have access to one and not have — and wait for mirv, that would not be unreasonable, but I’m going with the OS.

DR LOVE: Alright. Well, let’s finish out talking about the nursing considerations in patients getting mirvetuximab. Jennifer?

MS FILIPI: Alright. So I have another case for you all. This is a 64-year-old new grandmother with a platinum-resistant ovarian cancer. She progressed on platinum-based therapy this January with a large pelvic mass that you can see there. It was complicated by rectal bleeding, a lot of pain, hydronephrosis.

So we did molecular testing. HER2-negative, and she was found to be folate 1 receptor-positive. Oh, this is her and her new grandbaby and her son. He’s very cute. There’s another picture later.

So we’ve talked about how ADCs work, so I won’t get into that. This one, of course, targets folate 1 receptor. I also like to tell people that there is bystander effect, so just because all cancer cells don’t overexpress the folate 1 doesn’t mean the other cancer cells aren’t getting the drug as well. And it’s approved for platinum-resistant ovarian cancer with expression greater than 75%.

So kind of like PARP inhibitors, ADCs do have class effects, I guess, like the GI toxicity, blood counts and whatnot, but they also have very unique side effects. And I alluded to this earlier with mirvetuximab, the eye disorder. So this is when you want to pair with an ophthalmologist locally and try to get someone that can kind of help you through this. The most common side effects are blurred vision, dry eyes, irritation, redness. And so eye exams are required at baseline then every other cycle for 8 cycles and then as needed after that.

Neuropathy. That’s another big one with this drug, and a lot of patients have already had paclitaxel, right, so they’re probably coming in with some neuropathy, so you want to make sure you’re paying attention to that and dose reducing if needed.

This was an awful case of pneumonitis on an ADC. This patient ended up getting admitted to the hospital and going on steroids. She’s actually turned out well, but you can see those little ground-glass opacities in her lungs there. She came in in the morning, and her O2 sat had dropped to about I think it was 90 or 91%. And she said I am kind of short of breath. I was walking my dog this morning and couldn’t breathe very well. I guess so. Yeah, so that’s another thing to watch out for with this drug.

And the infusion-related reactions can occur as well. This is another drug we start over a long period of time, and if tolerated okay you can shorten the length of it.

Eye care during treatment. Of course, pair with an ophthalmologist. We have our patients do preservative-free artificial tears throughout the entire time they’re on this drug, every single day at least 4 times a day. And then we give steroid drops, as well, before and then up to 8 days afterwards. And this is just a little blurb we give to our patients in a packet just so they can keep track, because it is a lot of eyedrops if you think about it.

Back to our case. I’m happy to report that 3 cycles later she has had complete resolution of her bleeding. She has no pain. Her CA-125 is decreasing. She did have some blurred vision. I sent her back to the ophthalmologist, and she did have some eye changes, so we ended up holding her for 1 week and then ultimately dose reducing her. Her eye toxicity has resolved. She’s continued to tolerate it really well, and she actually has scans this week, so we’re keeping our fingers crossed for her. But there’s another picture of that grandbaby, and she also plays an instrument in her church.

DR LOVE: So I can really relate to the patient. I have a 1-year-old grandson, and I’m kind of curious, something that we’ve talked about in the past in ONS, is what are her personal goals. This is not a situation likely to be curative. I’m curious what’s important to her.

MS FILIPI: Taking care of that grandbaby is what’s important to her.

DR LOVE: That’s what I figured.

MS FILIPI: She told me the other day that her son drops him off at 3 PM and picks him up at 11 PM every day. I was like wow, can you be my mom?

DR WESTIN: I was going to say. She can get paid in Houston.

MS FILIPI: Yeah. Because she was so symptomatic that she wasn’t even able to pick him up, so controlling her symptoms and taking care and being with her family is what’s most important to her.

DR O'MALLEY: Neil, you made me very nervous there. You have a bunch of Gyn practitioners on and you’re talking about kids. I thought you were going to ask us where babies come from.

DR LOVE: So I want to thank our outstanding faculty. Come on back tonight, 6 PM, we’re going to talk about pancreatic cancer. Thank you so much.