DR. URSULA MATULONIS:
Hi, there! Welcome to the ASCO Post Roundtable Series on Updates in Gynecologic Oncology. I'm Dr. Ursula Matulonis. I'm the chief of Gynecologic Oncology at the Dana-Farber Cancer Institute. And joining me today are two of my wonderful and esteemed colleagues: Dr. Joyce Liu and Dr. BJ Rimel. Joyce, would you like to introduce yourself first?
DR. JOYCE LIU:
Sure. I'm Joyce Liu. I'm the associate chief of the Division of GYN Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.
DR. MATULONIS:
BJ?
DR. BJ RIMEL:
Hi! I'm BJ Rimel. I work at the Cedars-Sinai Medical Center and I'm the associate director for Gynecologic Oncology Clinical Trials.
DR. MATULONIS:
Awesome. Welcome. I think this is gonna be a great discussion. We're gonna be talking about, recent updates in gyne oncology and this is gonna be a case-based discussion. And we'll also be reviewing data that was presented at the Society of Gynecologic Oncology, 2021, which is finishing up recently. Lots of great data. Lots of interesting data. and I think we'll make the conversation very rich today.
So, our first installment will be discussing a case... this is case number 1. This is a 70-year-old woman who self-palpated an abdominal mass in 2018. CAT scan showed bilateral ovarian masses, omental caking and peritoneal carcinomatosis. She went to laparoscopy at that time by one of our gyne onc surgeons at Dana-Farber and was found to have extensive peritoneal carcinomatosis, omental caking and was not deemed a surgical, upfront cytoreductive candidate. Biopsy of the omentum showed high-grade serous carcinoma. She has some past medical history including hypertension, hypercholesterolemia. But these are both well controlled on medications. And she was found to have a germline BRCA mutation.
On the next slide, you can see her CT scans. She started intravenous carboplatin/paclitaxel. And after three cycles, her CT scan improved. She had reduction in peritoneal disease and omental caking, and her CA-125 reportedly dropped from 540 down to 30. She did go to interval cytoreductive surgery and at the completion of surgery, she was R0. And then, she finished up her carboplatinum and paclitaxel chemotherapy. Her CA-125 at the completion of treatment was 10.
So Joyce, do you wanna start about how you think about a patient like this with advanced cancer and how you bring in BRCA testing, other genetic testing, in terms of treatment options as maintenance treatment?
DR. LIU:
When we're thinking of frontline treatment of woman with newly diagnosed ovarian cancer advanced disease, the SOLO-1 trial, which looked at maintenance olaparib, was basically transforming. And I think that it is the standard of care that any woman with a BRCA1-mutated tumor should get PARP inhibitor maintenance after completion of therapy unless there is a medical contraindication to it.
Now, SOLO-1 trial showed significant progression-free survival advantage, and that reaches out to 2 years. And now with the updates from ESMO in 2020 and in SGO in 2021, we know that that benefit is durable. It extends out at least after 5 years of follow-up. We do not have overall survival data yet. But the magnitude of benefit that we see in terms of progression-free survival, I think, has been so striking that... You know, in my mind, for somebody with a BRCA-mutated ovarian cancer, we really have to think about PARP inhibitor maintenance.
DR. MATULONIS:
Yup. Yup. And obviously, yeah. No, Joyce, you correctly pointed out SOLO-1 and the 5-year updated data at SGO 2021 really showing, you know, in both low-risk patients as well as high-risk patients, there's a pretty significant magnitude of benefit. Low-risk patients meaning that they're stage 3, they went up from surgery and they were optimally cytoreduced. And the high-risk patients are everybody else. And I think, you know, the other trials of maintenance treatment... There's the PRIMA trial, which tests niraparib. And then PAOLA-1, which were for patients who at some point received Avastin or bevacizumab during their chemotherapy. And then, olaparib was added to bev versus no olaparib added to bev, as maintenance treatment. And I think there are distinct differences amongst the different populations that haven't been tested in these trials.
So, BJ, tell us about, you know, given this patient, the trial data we have, what would you recommend next as a specific PARP inhibitor?
DR. RIMEL:
So as Joyce mentioned, SOLO-1 was very transformative. So, olaparib was the PARP inhibitor used in SOLO-1 and that's 300 milligrams twice a day. I think there are advantages and disadvantages to each of the PARP inhibitors. Some of that, at least in my practice, comes with how to dose and dose reduce because a lot of patients have difficulty at the FDA recommended dose for all the PARP inhibitors. But for most of my patients that have a germline BRCA mutation, I start them on olaparib 300 milligrams twice a day. We try to mitigate the toxicities that we know are gonna come with that specifically fatigue and nausea being the two major ones that we see. I try to encourage my patients to preemptively take their anti-emetics. We work on bowel regimens because a lot of the anti-emetics have some constipating side effects.
And then for the fatigue, we're really starting to focus on counseling our patients in survivorship, which we hope... You know, especially on a PARP inhibitor for a BRCA-mutated patient will be a very long time that we have to encourage them to incorporate exercise and exercise tolerance building during that period that they're gonna be on this drug. Because we expect... For most of these patients, they're gonna be on it for 2 years. In some cases, they may be on it longer, but in an ideal world, everyone would be without evidence of disease and be able to come off at 2 years.
DR. MATULONIS:
Yeah. So, let's say, because obviously the trials... SOLO-1 looks at 2 years of olaparib. And then, if the patient at the completion of 2 years of olaparib really is NED, then the recommendation is to stop. And that's how the trial was designed. Now, in PRIMA, niraparib was initially started off as 3 years. But then, changed to, you know, continued treatment until progression.
Joyce, how do we think about that, you know, these PARP inhibitors are equivalent, I'm gonna say, equivalent in terms of efficacy. They obviously have different toxicities. So, why would you keep one going longer, as opposed to... In SOLO-1, you know, kinda hard to stop at 2 years.
DR. LIU:
So, I think this is a question that many of us have talked about this. What is the right length of time for somebody to stay on a PARP inhibitor? In the frontline setting, I think one of the attractions of using maintenance PARP inhibitors in the frontline setting is that the trials were designed so that people did not stay on the PARP inhibitors indefinitely. And while some patients and I think that we have all had hard conversations with patients because it's really frightening to stop something that you think is working especially if you're feeling really well on it and you've been on it, on it for 2 or 3 years.
But I think if you look at the trials and you know... I think about this a lot. If you look at the SOLO-1 curves, for example, you know... These are not clearly scientific things, but if you think about how the curves separate and the slopes of the Kaplan Meier curves, the greatest benefit and really the benefit that looks like you see from a maintenance PARP inhibitor... Certainly, for a woman with a BRCA mutation, looks like it's in the first 18 months or so. You know, most of the separation is in the first year and then you see maybe still a slight change in the slopes in the next 6 months or so. But then it... Everything looks about the same. I think one of the really reassuring things from the ESMO and SGO presentations from SOLO-1 was that they had five years of follow-up. And that, you know, even after people stopped, there was still durable benefit.
And I think as you alluded to, Ursula, we have to think about what's the flip side, what's the downside of keeping people on PARP inhibitors for an indefinite period of time. When we talked about, you know, there are tolerability issues. There is, you know... Although it has not come out on quality-of-life sort of studies, that have been associated with these trials, I think for all of us who have treated women with PARP inhibitors, there's something different. There's fatigue. There's just... You're just not at 100%. And when people stop, they feel better. But I think that the other component of it that we don't, that we talk actually a fair bit about is, you know, is the risk that somebody could be more vulnerable to developing MDS or AML or something because they have prolonged exposure to PARP inhibitors. And I think we honestly don't know the answer to that question, but it's a risk we have to be really aware of.
DR. MATULONIS:
Right. And I think at least at this point, again, the trials are hard to totally compare, but the risk of AML, MDS is less, for a trial like SOLO-1 where it approaches around 1%, versus in the second case that we'll talk about where we're starting to see risk of AML, MDS, that are, you know, 7-8%... they're higher.
BJ, so, we talked about two things with you. One is for patients who are on a PARP inhibitor, the FDA guidelines say that when you start a patient on a PARP inhibitor, there are different requirements about checking blood counts. And the FDA requires for olaparib in the package insert that patients have a CBC check at least once a month for the first year. For a drug like niraparib, it's weekly at least, for the first month, and then up to the clinician.
How do you manage patients from a blood count standpoint? You know, patients are coming off chemotherapy. It's in their cancer. Kinda low... and this is again... This is regardless if the patient is BRCA mutation or not. But how do you follow-up patients over the first year to 2 years in terms of blood count checks? And since... You know I have a lot patients who are wanting their CA-125. So, what is happening is that when they get their CBC checked, they also get a CA-125 checked. How often do you do CA-125 checks?
DR. RIMEL:
Those are really great questions. I think that in our practice, we try to give the patients adequate time to recover from their chemotherapy before we start the PARP inhibitor. So, I require that they come in, no earlier than 6 weeks post their last cycle of chemotherapy, to make sure that they have a normal CBC before we start. Patients sometimes are really anxious and wanna just start the minute they feel that they're ready to go. But we need to be really careful about managing that and those expectations especially for niraparib. Those weekly blood tests are incredibly important because there can be a steep drop-off especially in platelets around the second week of therapy. If the patients gonna get that thrombocytopenia and you wanna find it, and you don't wanna find it on Friday at 5 PM.
So, we've really shifted our management of patients to having them not take their drug on the day of their CBC until they hear from us to make sure that we don't miss an opportunity. It's just an implementation issue for us. And I imagine for others as well. To make sure that we don't miss an opportunity to stop a drug that needs to be held for a while.
So, CA-125 is really complicated, right? And I think that we get back to some of the old data when we talked about CA-125 as a marker for recurrence with the ovary. And that early detection of a recurrence by CA-125 didn't improve survival. When evaluated based on versus people treated only on symptoms, we didn't have their CA-125 checked. I think that in the modern era it's really hard for patients to live without that certainty or feeling of certainty. So, a lot of times what we try to do is say, "Look. We'll check it every time you come in for the first 3 months. And then, if it's good let's just not look again!" (laughs) until we get to like a month, 6-ish. So, we're kinda getting back to that every 3 months like we would.
It can be challenging to have that conversation 'cause a lot of patients feel a sense of safety with a normal number. But I try to remind people that, you know, a negative test is just a... It's just a number. And sometimes when it comes to doing labs that don't mean a lot and maybe don't change the patient's outcome, we're a little bit burning money, which we're trying not to do-
DR. MATULONIS:
Yeah.
DR. RIMEL:
... uh, in medicine. So, that's another area that we just... We have lots of conversations and lots of, you know, chats about symptoms and things like that.
DR. MATULONIS:
Yeah. How about CT scans? Do you... Or, or PETs? Do you incorporate any regular, regularly checked interval radiographic imaging?
DR. RIMEL:
That's a great question. So, I don't in my practice. I try not to for patients that have CA-125 as a marker of their disease. For patients for whom CA-125 was never a reliable marker of their presentation or response, then those patients get a CT scan from me about every 12 weeks for the first year or so. Just basically the same assessment of a response to treatment that we would do with the CA-125.
DR. MATULONIS:
Joyce, I know we really... If the patient has, has a BRCA mutation, germline BRCA mutation, so I think the treatment is obvious to use a PARP inhibitor as maintenance. But for patients who are HRD, via test, or HRP: so meaning HRP and BRCA wild type. How do you differentiate those groups and how do you clinically make decisions about offering a PARP inhibitor any PARP inhibitor, in those categories of patients?
DR. LIU:
I think as you said, for somebody with a BRCA mutation, it feels like the answers are quite clear. The hazard ratio is 0.3 and that's, as you pointed out, consistent across all of the trials. So, PAOLA-1, PRIMA, SOLO-1 for somebody with a BRCA mutation. When you don't have a BRCA mutation, I think it is a little less clear what is the best thing to do. And I think that this is where it really becomes a conversation with the patient and sort of what their priorities are. What we know about PARP inhibitor maintenance regardless of whether it's in the frontline or in the platinum-sensitive recurrence setting for women without a BRCA mutation is that it will provide PFS benefit. And I'm not talking about in the combination with bevacizumab 'cause that's a different can of worms.
But it will provide PFS benefit, but there has never been evidence that it provides OS benefit for any of these women. And margin of PFS benefit, you know, by doing HRD testing, you may be able to distinguish some women who are more likely to gain larger amounts of benefit versus somebody who might have a more limited amount of benefit. But HRD testing is not perfect. And so, it's just sort of a piece of information that you can use to provide a little bit of guidance and maybe a little bit more information, but it's not sort of like a black and white measure like you'll benefit and you won't. So, I think big picture wise, to me, I think about as if you don't have a BRCA mutation, the use of a maintenance PARP inhibitor will provide some amount of PFS benefit that comes at a cost. That cost can be in terms of quality of life 'cause you have to have the side effects of PARP inhibitors. You're adjusting. You have to go and get those weekly or sort of monthly blood tests.
And, it comes with some level of risks, you know. Maybe by going on a PARP inhibitor you get a complication. Maybe you are, for some reason, more vulnerable to developing MDS or AML and the PARP inhibitor kinda kicks you into that. And so there's level of risk to it. And so I think for these patients it's really a discussion. "What is it that's most valuable to you? Is it time off of sort of feeling cancer-free while you're on this pill? Is it time away from us completely? So don't take anything and have sort of a period of time when you're truly in remission and you feel like you're not tethered to us the same way, by having to take a maintenance PARP inhibitor." And so that's... That's how I think about it at this point.
DR. MATULONIS:
Yeah. That's great. Two points I wanna make before we wrap up this case. One is that just to, to tell the audience, to remind the audience that all of these trials around PARP inhibitor maintenance are for patients with advanced high-grade serous or high-grade endometrioid, but really mostly high-grade serous cancer patients who have underlying homologous recombination deficiencies associated with their cancer. So, this is not for low-grade serous or low-grade endometrioid tumors. And then, say... And then, those patients have to have their cancer be in response to chemotherapy to be considered for maintenance treatment, and all the maintenance trials for either newly diagnosed high-grade serous or recurrent high-grade serous cancers all have those as eligibility criteria.
And the second point is around PAOLA-1 and how this trial added olaparib to bevacizumab versus bevacizumab alone. The key is really for, for any patient who gets at least some bevacizumab, uh, with upfront chemotherapy. And obviously, in this trial, just like we've seen with, with the other studies, there's a benefit to adding the olaparib to bevacizumab; certainly in the BRCA mutated population. Certainly in the HRD population, there is no benefit to adding the PARP inhibitor to bev with patients whose tumors were HRP. So, that does not have an FDA approval.
BJ and Joyce, any last comments before we wrap up this case. BJ?
DR. RIMEL:
No, I don't think so. I think we've sort of established that at least amongst us the germline BRCA patients get a PARP inhibitor maintenance in frontline setting. And I think that that's probably pretty standard throughout our treatment community.
DR. MATULONIS:
That's good. Joyce?
DR. LIU:
Yeah. I would add to what BJ was saying is that, you know... I think that highlights the importance of doing testing when people are getting frontline therapy. So, do germline testing and I would also add that you should consider somatic testing because we know that 5-6% of patients have somatic BRCA mutations. And although they were not wrapped up into the SOLO-1 study, there are some of those patients in the PRIMA study whom we think that that those patients will have also a very large margin of benefit.
DR. MATULONIS:
Great. Sounds good. So, this, this brings us to the end of the first case and please see the other segments for further discussion about the latest data in gynecologic oncology or visit ascopost.com.
