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DR. URSULA MATULONIS:
Hi there. Welcome back to the ASCO Post Roundtable series on Updates in Gynecologic Oncology. I'm Dr. Matulonis from the Dana-Farber Cancer Institute in Boston, Massachusetts. And I'm joined here by two of my incredibly esteemed, uh, wonderful, terrific colleagues, Dr. Joyce Liu and Dr. BJ Rimel. Joyce, would you like to introduce yourself?
DR. JOYCE LIU:
Sure. I'm Joyce Liu. I'm the Associate Chief in the Division of GYN Oncology here at Dana-Farber Cancer Institute in Boston, Massachusetts.
DR. BJ RIMEL:
Hi I'm BJ Rimel, I'm a gynecological oncologist at Cedars-Sinai Medical Center in Los Angeles and the Associate Director of Clinical Trials for GYN oncology.
Great to welcome you back. And the second case that we're gonna talk about is a patient who has recurrent platinum-sensitive ovarian cancer. This is a 65-year-old teacher, and she was diagnosed with stage three high-grade serous ovarian cancer in 2013, underwent surgery, was NED at surgery, received carboplatin/paclitaxel as adjuvant treatment. And also during her initial testing and workup was found to have a germline BRCA1 mutation. She has hypertension and is on three medications for this. She was in remission until 2017 when her CA-125 rose to around 200 and a CT scan showed small volume ascites and omental nodularity, all consistent with recurrent ovarian cancer. So this brings up the topic, and again, obviously, we're going to weave in again the genetics of the tumor, also the histology of the tumor, when you're making decisions about how do you treat a patient with platinum-sensitive ovarian cancer in terms of the choice of chemotherapy, and also whether or not to use maintenance treatment. Joyce, do you want to just give us a few points about these two questions?
Yeah, so I think, you know, when we think about what choice of chemotherapy we use for somebody who's platinum-sensitive, meaning that their cancer has come back at least 6 months after platinum, I think that most of us would agree that you want a platinum-based backbone. But what you pair that with is often a question of what the patient has had before, what side effects they have and what sort of is acceptable to them in terms of a toxicity profile. And so I think the options are really carboplatin with paclitaxel, carboplatin with pegylated liposomal doxorubicin, and then, carboplatin together with gemcitabine. And those are probably the three main options that we think about, with or without bevacizumab, in a setting of a platinum-sensitive resistance—sorry, platinum-sensitive recurrence. And, you know, when I think about these options, this is how I discuss them with patients.
We think about, you know, hair loss, neuropathy, schedule of administration, carboplatin and paclitaxel is every 3 weeks, carboplatinum and liposomal doxorubicin is every 4 weeks, so it's a slightly more extended course. Paclitaxel and gemcitabine is 2 weeks out of every 3, that's a slightly harder regimen. And so I think that these are the things we take into consideration. In terms of maintenance therapy, I think we'll probably get into a larger discussion of this. I think that, you know, when I think about maintenance, one of the things is, are you starting somebody with bevacizumab? I think people vary on how they think about this. I actually don't tend to use a ton of bevacizumab in this setting because I tend to save it for a later setting, but if you start somebody on bevacizumab, you'll continue them on bevacizumab maintenance. If you haven't started them on bevacizumab, then the question comes up, is this somebody who might benefit from PARP inhibitor maintenance?
Yeah. BJ, any additional thoughts? So she ended up just going on carboplatin and Doxil. Obviously she's, she's more straightforward because she has an underlying BRCA1 mutation, she's never had a PARP inhibitor. So here it's pretty straightforward, but let's say the patient, you know, maybe doesn't have a BRCA mutation. Maybe you haven't done her HRD status and she's a few years out. Does that change your decisions around maintenance? If you know for sure she does not have a BRCA mutation, but she's still high-grade serous, but she doesn't have a BRCA mutation.
I think without that HRD testing in this line of therapy, it doesn't necessarily change my decision, but it really modifies how I counsel patients. For a patient like this who had a five-year disease-free interval that decides to go on carboplatinum and Doxil, which, or liposomal doxorubicin, which I would just offer one more little caveat to. That is a regimen I really liked because of the decreased risk of carboplatinum allergy, especially in a patient that I think is likely to be platinum sensitive again, this patient's very likely to get another platinum and I would love to be able to continue to give them carboplatinum. So that's a regimen I really like in a platinum sensitive setting. So for this patient though, how do I counsel her without that information? I would have to, you know, say that you might have as little as, you know, 2.7 to 3 months benefit from a PARP inhibitor maintenance versus you could have maybe even 9 to 12 months benefit from PARP inhibitor maintenance, you know, kind of depending on which direction to go. I think that's a very hard conversation, so I prefer to test these patients for HRD, if they haven't been previously tested.
Yeah. So, and now, you know, those are great thoughts. So now with ASCO and with SGO 2021 we have additional information that we can impart to our patients to help them make decisions. One is around the risk of AML and MDS, and we started to talk about that during that first case. And now in two trials, in SOLO2, and in NOVA that we see an increased risk of development of AML or MDS with use of a PARP inhibitor in patients with an underlying germline BRCA mutation. There still is a risk with patients who have a germline BRCA mutation who did not get the PARP inhibitor, and that's even more elevated than patients who are BRCA wild-type, so we have that information, and then secondly, NOVA reported out overall survival results as did SOLO2.
So SOLO2 was at ASCO last year, ASCO 2020, showing about a 13-month trend towards an improval in survival for patients receiving olaparib who had a germline BRCA mutation in SOLO2. And then for SO-, for NOVA, there was no overall survival benefit, obviously certain caveats existed, but the bottom line is there was no overall survival benefit for non-germline BRCA-mutated patients. And there was again, a trend towards OS for the germline BRCA-mutated patients who received niraparib. BJ, I want to ask you first, how does this information help you make decisions with patients in, should I use a PARP inhibitor, yes or no?
I think that for me, with careful counseling, a germline BRCA mutation carrier, who's not received a prior PARP inhibitor in the frontline, who's PARP naive now, platinum-sensitive with a complete response and the, the trend towards overall survival benefit with the addition of olaparib, I would encourage them to consider olaparib as a good choice for them to prolong their survival, but also to improve their disease-free interval. For a patient that does not possess a germline mutation, even if they're HRD-positive, I think that the counseling needs to center around the risks and benefits to that PARP inhibitor and the duration of that treatment. Is it just enough to know that you're more likely to not have to be on chemo for a few more months, or is the opportunity of being off all treatment altogether better benefit to the patient's well-being than being on the PARP inhibitor maintenance? And I think that that's one of the, I mean, I was really hoping to see an OS benefit for HRD patients in this setting because the PFS looked so exciting, but, you know, we didn't see that, and so I think it really comes into counseling the patients about what it truly means to have a disease-free interval versus a prolonged maintenance interval.
Yeah. I agree. I mean, information is helpful. Joyce I want to ask about the, couple of points. One is that, in this setting, we've got three PARP inhibitors that we can use. Olaparib, niraparib, now there's rucaparib. So question one is, how do you make decisions about choosing one of those three? And then secondly, and I've noticed this a few times now, since the AML and MDS risks are coming out, that, you know, these three trials in maintenance for recurrent relapse platinum-sensitive patients are to treat, use the PARP inhibitor until relapse or toxicities, but I've definitely seen some women recently where the oncologist has actually recommended truncating treatment at 2 years, sort of analogous to the SOLO1. But that's not how the trials were designed. So comments on one, about choice of PARP inhibitor, and then secondly, how long do you usually treat patients in this setting?
Yeah, so I think that the choice of PARP inhibitor to me is about side effects. It's, you know, I don't think we have convincing data from any of our trials that these PARP inhibitors, are different from each other in terms of effectiveness. And so I think that it really comes down to side effects, and I think BJ alluded to this and spoke really nicely about this when we talked about the first case, but, each of the PARP inhibitors has its own unique profile. So olaparib is a twice-daily medication, it can cause potentially a little bit more anemia than rucaparib and niraparib can, and it has some interactions via CYP, the cytochrome P450 system. And so sometimes you need to make adjustments for other medications the patient might be on.
Niraparib is once-daily dosing based upon platelets and weight, but can be a little bit more prone to causing hypertension and of course the big side effect of niraparib that seems to distinguish it from the other PARP inhibitors is it can cause this thrombocytopenia, that happens about somewhere between 3 to 5 weeks after starting, and while the weight and platelet dosing has helped ameliorate that as a mitigation for it, there are some patients who will get very profound thrombocytopenia, dropping into the single digits and you have to watch them closely. Weekly labs for the first 8 weeks that you start them on, so that you don't get surprised.
And then rucaparib, again sort of has its own profile. It has more interaction with the renal system, so you can have this lab-based elevation in the creatinine that's not a true reflection of decreased renal function. You can get some LFT rises about 2 or 3 weeks after starting. And so these are sort of things that I think about in terms of, you know, what are the side effects of the PARP inhibitors? What are the things that my patient might be vulnerable to? And that helps guide me in terms of which ones I'll select. In terms of the MDS/AML risk, I think it's very challenging. We don't know in the recurrent setting that a truncated course of PARP inhibitors is, has equivalent efficacy to sort of, you know, indefinite treatment because the trials were all done with indefinite treatment. We do see the SOLO2 trial reported in women with germline BRCA mutations an almost 8% risk of developing AML or MDS, and in the NOVA trial it was just over 6% or close to 6%. And those are clearly concerning numbers.
I think when I think about it, one of the things I don't know, because the data in the frontline trials are much lower risk, is whether this increased risk is because these patients had prolonged exposure to PARP inhibitors i.e. indefinite, or is it the interaction because these patients were in the recurrent setting and have had more prior chemotherapy? So it's the prior treatment with chemotherapy, a recurrent course, at least one of chemotherapy, and then PARP inhibitors that makes it an increased risk of MDS/AML, as opposed to because they got longer courses of PARP inhibitors.
Yep, yep, agreed. BJ, last question before we start to wrap up this case. So in terms of maintenance strategies, we've talked about platinum-based chemotherapy. Obviously, there's the possibility of adding bevacizumab to platinum-based chemotherapy, or the third option is platinum-based chemotherapy, then maintenance PARP inhibitor. Would you ever sort of mix together option two and three and add and give a combination of a PARP inhibitor plus bev as maintenance treatment? I've seen that done and just wondered what you do.
I personally haven't done that yet, but I would leave open the possibility that for a patient that presented in the recurrent setting with large volume ascites or recurrent plural effusions, that I may be more inclined to continue a bevacizumab that I started to help mitigate some of their initial presenting symptoms. And especially if that patient was BRCA positive, then I wouldn't necessarily want to stop the bevacizumab, and I know I'd want to give a PARP inhibitor. So that's a situation that hasn't happened to me yet, but I think that I would feel very confident that I would have a good rationale for the combination of the two in the absence of any real data.
Yeah. Yeah. There's just not that data yet. But you're right, it certainly seems like a good thing to do, but I also haven't done it yet either. So as we wrap down and we wrap up this case Joyce, parting comments? Anything else you'd like to say?
I think that, no, I mean, I think the one thing I would point out is all of our discussion is in the setting of patients who are PARP inhibitor-naïve. And we do not know yet what the value is of coming back to PARP inhibitor maintenance, in somebody who has already received frontline PARP inhibitor maintenance. Those data are simply not available to us. There is the OReO trial that is ongoing that studying olaparib in patients who have previously received maintenance of olaparib, but we just don't have those answers yet. And so that would be one caveat I would have about our discussions.
Yeah, I agree. Well, we'll meet up, in maybe a year or two, and we'll have more clinical experience, at least, but certainly, hopefully more data too. BJ, closing thoughts on this case?
Just to, you know, go back to the initial choice of platinum doublet, taking into account the patient's symptoms, what they've been treated with prior and, just remembering also, this is a patient that presented with potentially disease that somebody might want to resect after 5 years of DFI, and we have GOG-213 to help give us some guidance that we probably don't need to get in there surgically and manage that.
Absolutely, that's a really good point. And obviously if the patient had a low-grade serous cancer, we would not think about adding a PARP inhibitor, but that's the kind of patient you'd do a platinum doublet or add bev to the platinum doublet. Great. Okay. So that wraps up this case, and please see your other round table segments for further discussion about updates in gyne onc or visit ASCOpost.com.