Activity Transcript

Donyika Joseph, PharmD, BCOP: Hi everyone. My name is Donyika Joseph, and I'm a clinical pharmacy specialist in the gynecology oncology department at the University of Texas MD Anderson Cancer Center. Welcome to this program titled, "Managing the Care of Ovarian Cancer With PARP Inhibitors: A Managed Care Approach." Joining me today are Laura Bobolts, PharmD, a board-certified oncology pharmacist with Onco Health, and Dr Kathleen Moore, a professor in the section of gynecology oncology at OU Stevenson Cancer Center and Oklahoma University College of Medicine. Welcome.

Ovarian cancer is the 7th most common cancer in women worldwide, and it affects about 19,000 women a year. Typically, this is a cancer that we find at later stages, unfortunately, so around stage 3 or stage 4. In the past these patients were dispositioned to surgery followed by chemotherapy or neoadjuvant chemotherapy, surgery, and then adjuvant chemotherapy and then they went on to surveillance. Unfortunately, 70% to 80% of patients do progress after their frontline treatment, which then leads them to have to be on chemotherapy again.

Recently, we have been using maintenance therapy for these patients, and this has been something that has given us the ability to prolong the time these patients have off chemotherapy and potentially improve their quality of life. Dr Moore, can you comment on the genetic and biologic heterogeneity of ovarian cancer and its implications for patient care?

Kathleen Moore, MD, MS: Of course. We are, I think, at the tip of the iceberg for really understanding high-grade serous, well, let's just say epithelial ovarian cancer. Which when I was a trainee back longer ago than I would like to admit at this point, we just lumped all epithelial ovarian cancers together in clinical research. So high-grade serous, low-grade serous, which actually wasn't even a thing back then, clear cell, mucinous, endometrioid grade one through 3. All of that was lumped together as ovarian cancer.

We have increasingly understood that is absolutely not true. We have TP53-driven tumors, which are largely our high-grade serous and some high-grade endometrioid. Clear cells are really considered kind of a separate entity, and we are trying to develop agents for that class of tumor. Mucinous unfortunately remain a very difficult class of tumors to treat. Low-grade serous is its own thing and has its own kind of endocrine based treatments, which we never use in high-grade serous. Then we're working on grade 1, 2 endometrioid.

That's just looking at it by pathology. Then you layer onto it the molecular differences, and we know the most about high-grade serous. We understand the implications of a BRCA-associated cancer, either germline or somatic. It's about 20 to 25% of tumors have some BRCA alteration. Another 10% have epigenetic changes like methylation of the promoter, which basically renders the tumor absent of the BRCA protein so it's like having a BRCA mutation without the mutation. Then there's another 20% of tumors who for a myriad of reasons struggle to fix their DNA, and that leaves them more apt to respond to DNA damaging therapy such as platinum or poly (ADP-ribose) polymerase (PARP) inhibitors.

Then there's the rest that have cyclin E amplification and MEK and mismatch repair, not very many. And so how best to treat that group of tumors, which is about 40%, is still a nut we have to crack, and that's just talking about high-grade serous. And I can talk a whole hour about low-grade. I can talk additionally about endometrioid. So these tumors at diagnosis are incredibly different from one another and over time with temporal and spatial heterogeneity, they become even more challenging to characterize and treat.

How does it implicate treatment or inform what we do? Well, in the front line. if we do identify tumors that are associated with BRCA the standard of care now is PARP inhibitors for switch maintenance. What that means is that the patients still receive what we call induction or adjuvant or neoadjuvant chemotherapy with a platinum, mainly carboplatin and a taxane, mainly paclitaxel for some number of cycles, minimum of 4, but usually six to eight and there'll be a surgery in there.

At the end of that, usually patients are in some kind of response, either a complete or partial response. And so if we know there's a BRCA mutation, either germline or somatic, the standard of care is a PARP inhibitor. And in the studies where we've studied this or evaluated this, the use of a PARP inhibitor for 2 to 3 years decreases the hazard for progression or death by 60 to 70%. And we do not have long enough follow-up yet to really comment on median overall survival. But in SOLO1, which is the first study to report out, at 7 years, we have about 43% of women randomized to olaparib still without disease. So they've been off therapy for at least 5 years and they have not recurred and that's compared to less than 20% in the placebo arm. Even though in that placebo arm they may have gotten a PARP later, appropriately, because they didn't get it in the front line.

But the point is we don't catch them up by waiting, so don't wait. Frontline is where we use it and you can use it with or without bevacizumab. If we don't find BRCA-associated cancer but we find evidence of other vulnerability in the tumor, we term this homologous recombination deficiency (HRD) or loss of heterozygosity depending on which FDA assay you use. In my opinion, PARP inhibitor here still is the standard of care, although there's probably some equipoise around that when we better characterize how homologous recombination deficient a tumor is. Some are a little, some are a lot. But when you use PARP inhibitors here in the same way as we do in BRCA-associated cancers, we see about a 50% reduction in the hazard of progression or death. So not as strong a signal as BRCA, but still pretty darn strong.

And then when you have these tumors that have neither BRCA or HRD, here it gets a little more puzzling. Some studies will show about a 32% reduction in the hazard of progression or death with use of a PARP. Others have demonstrated kind of minimal effect as compared to bevacizumab if used in that setting. Overall, we know that this is a very poor prognostic marker for these tumors to be identified as HRD test negative, the progression-free survival curves just look different. They're much more vertical. So it is a prognostic factor and we can nudge it out a little bit with PARP inhibitors. But the truth is we really just need to understand better why these tumors are really good at fixing their DNA and how we counteract that piece and come at it with new agents.

For women who did not receive a PARP in the front line and recur and are what we consider appropriate for re-treatment of platinum. And their tumors re-respond to platinum, they're also eligible for a PARP inhibitor. And PARP inhibitors here work very well just like they do in the frontline. The limitations are that we're no longer curable, we're no longer expecting cure once we've recurred, as we are now somewhat expecting some cures in the frontline, which is why we think frontline is the best place to use PARP inhibitors. But they do work well if someone has missed the opportunity in the frontline and they respond to platinum. Again, they're indicated for responders as switch maintenance.

But the other difference is that there's no expectation that you're going to stop the PARP. All of the studies were done with treatment of PARP to progression. And so patients could be on PARP inhibitors for years sometimes, which I guess is a good thing because it means they haven't recurred. But there are probably secondary financial and physiologic adverse effects from years of PARP that, again, we offset with use in the frontline.

Interestingly, in the platinum sensitive setting, the requirement that patients' tumors have to respond to platinum was the most important biomarker even over BRCA, HRD, etc. If the tumor shrunk to platinum that told you the patient was going to get benefit from the PARP. And of course there's a gradation of benefit from BRCA to HRD to non-HRD, but everybody benefited, which is why in that setting the approvals are not related to a biomarker.

Dr Joseph: I think that's kind of where we were at first. First, we were using it in the recurrent setting. But then we noticed that people weren't tolerating them as well in the recurrent setting or their counts were starting to bottom out and we were like, we should have used it kind of further upfront. So now we're really trying to push for PARP up front in our patients.

Dr Moore: Absolutely. That is what we should be doing.

Dr Joseph: Dr Moore, do you have any comments about monitoring these patients or anything that we should be worried about when we're dosing the patients? Any adverse events that you would kind of pinpoint to look out for?

Dr Moore: When you're starting a patient on a PARP inhibitor, really setting expectations is key. Because remember, these patients will have just finished six or eight cycles of platinum-based chemo. They're excited to be done with chemotherapy. They're often tired, they have some neuropathy. You have to have the conversation about maintenance ahead of cycle six so that they understand what's coming in that length of time. So really having those conversations starts really the moment you get the biomarker back and you have a plan for that maintenance so that the patient really understands what is ahead of her. You can't spring this on someone post cycle 6. Like, oh, you thought you were done? Ha ha.

And then there's setting expectations just about the PARP inhibitor. These are very well tolerated medicines, but they do have side effects. And so for a lot of our patients, they're like, Oh, it's a pill. That's so great, it's not intravenous, this is going to be fine. And if you just send them off with their prescription for whichever PARP inhibitor you're going to use, we're actually going to run into trouble. Because they do have side effects, and the class effects are very common but low-grade nausea, very common but low-grade fatigue, those are the 2 main things. And then they can get constipation and some dysgeusia.

So you have to set that expectation. And what I tell patients, and we have this from clinical trial data, is that the nausea is quick. By 3 days in, if you're going to have the nausea, which almost everyone does, you're going to have it. My personal practice is I send patients with a prescription and I just have them take it to try and not break the cycle but just eliminate it so that they get through that first 2 months. Because the first 6 to eight weeks are the worst. The nausea kind of peaks up to week 4. The fatigue kind of peaks up to week 4 to 6 and then things start to come back down.

So by the time they're coming in for that pre-cycle 3 visit, they've settled back down and you can actually withdraw the antiemetics that you've used in a lot of patients that are not on all these medicines the whole time. But you have to tell them that the first 2 months might be kind of rough. They just feel like a wet noodle. They'll tell you like, "Oh, I just quite can't get myself going" and "I can do it, but it's so much effort to go shopping." And "I thought I was going to feel better" because they were so hoping to feel better off chemo. And then we give them this PARP.

So, setting expectations is really key. The other thing to remember is that you don't want to start the PARP 3 weeks after their last cycle of chemo. That's also a recipe for not staying on a PARP. You just need 6 to 9 weeks off from that last dose. So I usually see them back 3 weeks later. We do PARP counseling again, then I get them authorized and they're starting at week 5 or 6 because they've got to have some time to just recover from the chemo.

Now once you start them, you do have to monitor their counts. So the class effect is anemia. So you'll see grade 3 anemia. So a hemoglobin less than eight in about a quarter roughly. It varies a little bit across the PARPs, but if you just remember it's a quarter, and about 2/3 of those, not of all patients, but 2/3 of that quarter will need a transfusion. Others you can kind of hold until it comes back up. So that you have to watch for.

Now the other kind of helpful thing is when you're thinking about, I try to do this before chemo now even, but if I forget, I do it before PARP. I just assess all my patients for iron deficiency, B vitamin deficiency. We have a lot of nutritional deficiencies in Oklahoma and it's just a ... vitamin D, which doesn't matter for anemia, but still we find it. So I try to replace all those things before I start the PARP or as I'm starting the PARP to minimize how severe the anemia will be so I can try and keep them out of that grade 3. So pay attention to that.

So you have to follow that monthly for rucaparib or olaparib. And then once you've been on it for a bit, usually by about a year you can back off on the labs. But they need monthly labs. For niraparib you have to do weekly because that's the one with the risk of severe platelets. It's about a 13% risk of grade 3 or higher platelets. And so you have to assess that weekly when you start for about a month, 4 weeks to make sure they don't drop.

And if they do start to drop, you got to have someone that's on that and calls them and says, Hold your niraparib. Because you don't want to find that on a Monday that their platelets on Friday were 87 and you didn't stop the PARP because then they're going to come in and they're going to be like 10. So it's really important with niraparib. It's a safe drug to use, but you have got to check the labs. And if patients are pretty stable after kind of 4 to 6 weeks, then you can just go to monthly labs.

If you drop the dose because of the thrombocytopenia, the weekly labs have to start again and so you're sure that it's stable and then you can back off. So there is a little bit more surveillance with niraparib that you have got to do or your office staff has to be all over it to make sure that that's safe. And that's really how you monitor them. I think things that should be just things that make your antennas go up are patients who are on olaparib or rucaparib, for example, they're having repetitive drops in their hemoglobin. So repetitive grade 3 drops despite modifications. That's the one that I'm going to get worried about and probably have my hematology colleagues see.

I have a very low threshold for sending consults to heme and making sure that someone's bone marrow is okay. Because the last thing I want to do is continue, unless it's BRCA and I might cure someone, that's a hard decision. But if I have someone whose bone marrow is a little more acellular, the things that they look at, they're like, eh, it's not MDS, but it's not normal either. And you're month 20 of PARP, I'm going to stop the PARP and just say, I think we're probably good there, and not take them to 2 years. So repetitive drops for anemia, patients who have significant drops in ANC or platelets, outside of niraparib where you expect that, but the other 2 you should not see a lot of grade 3 or 4. So someone that's riding with their ANC at 750, I get worried about those folks and I get a consult. So I think you have to just have your antennas up a little bit for those rare but not impossible side effects.

Dr Joseph: That's a great point. And I think 1 thing that makes me think about is how it's a team effort. Because I know for us, we have with niraparib, we have our nurses do a weekly phone call for the first month with the patients. They review their complete blood count, we all make sure it's safe to continue. And then we have our primary care providers who are maybe closer to the patients if they live far away, they're keeping an eye on them too. Everyone's kind of all eyes on the patient, especially when they first start.

And then I like what you said about setting expectations. I think one thing that I can uniquely bring to my team is kind of reminding them that these medications are not without socioeconomic costs. Some of these patients, the cost burden is so high for them that we don't even think about it. We're just like, yes, this is the perfect drug for you, but we don't kind of take the steps to figure out can you afford it? Are there any ways that we can make this more affordable for you?

And I'm sure, Laura, you can probably speak to this too. I know a lot of the insurance companies have a managed care pharmacist with them and I'm like, do we have patient assistance? Are we doing split fills? What is the plan so that we make sure that we're not kind of essentially wasting this patient's money and starting them maybe on a dose that they can't tolerate and then they have to end up discontinuing and they have all this extra medication. I think just explaining to them all the side effects is pretty important as well.

Dr Moore: Agreed.

Laura R. Bobolts, PharmD, BCOP: Absolutely. And just to add to that, the financial toxicity of these therapies can be really high for our cancer patients. So that's where split fill programs come in to try to buffer the patient, protect them from that in case they have toxicity and cannot continue on their medications. Split fill is where, say, half a month of therapy is filled up front, 15-day fill. Once the patient tolerates it, another 15-day fill. And can occur for the first 1 to 2 months depending on the payer.

It has its positives in reducing financial toxicity, but also drawbacks, as many can acknowledge, because you need to make sure you have a great specialty pharmacy that can get that medication out fast and deliver to the patient because we do not want to delay care and delivery of that medication. So very important to look out for the patient, make sure they receive their medication on time. But the financial toxicity has to be looked at as a whole.

Because there was 1 study by [Katherine] Esselen and colleagues looking at over 308 pathologic oncology patients. And among the ovarian cancer patients, 47% reported that they had moderate to severe financial toxicity. And when you drilled into those with severe financial toxicity, they found that almost 4 times higher rate was seen of the patients changing their spending habits. And then patients that had severe financial toxicity were over 13 times more likely to borrow money from a family member.

So, these patients get put in unusual circumstances where they may have to reach out to family members, they may have troubles paying their bills, and we got to acknowledge that and see what good we can do for our patients. Whether it's those financial assistance programs, whether it is grants and foundations that may be available to the patient to help them ensure that they can cover the cost of their therapy. Because if the patient can't afford it, not likely to take the medication, not likely to go through all the extra hurdles to find how to secure that coverage.

Dr Joseph: I think that's super important because when I consent the patients or educate them, one of the things I talk about is the cost. And I talk about, this is our plan, we're going to run it through your insurance. If the copay's too high, we can apply for patient assistance. And then sometimes their cash price is still in the hundreds or thousands. But I always remind them, this is something we want to ideally keep you on for 2 to 3 years. So if this isn't something that you think you can sustain for 2 to 3 years, please let us know because we need to try to either pick a different medication or we need to try to think of a different plan. So, I think setting that at the beginning so that they know the goal is long term on this medication. It's not just like a one and done kind of thing.

Dr Bobolts: You got it and thank you for that. Honestly, from bottom of my heart, for having those conversations with the patients up front. It's so paramount to making sure that they can continue on that medication, they can pay for the medication and derive the benefits from that medication going forward, as you mentioned, for years to come.

Dr Joseph: Laura, are there any other, coming from a managed care perspective, any other resources that you think that we need to know about or things that we need to be looking at when treating these patients?

Dr Bobolts: Oh, so I have a lot of tricks in my bag. Coming from my days in clinical practice, I didn't know what I knew about insurance companies and how to secure insurance coverage. I really wish I had that managed care training back then, because if it was an expensive medication, I was kind of going like this and I might even delay the patient receiving the medication because I wanted to make sure that coverage was secured. Now today, there's so much that can be done to expedite that decision for the prior authorizations so that we don't delay care for cancer patients.

But in general, the tricks in my bag really are knowing your resources. And many clinicians may not know that for Medicare members to secure insurance coverage, we're looking for FDA approvals for the therapy, we're looking for National Comprehensive Cancer Network (NCCN) compendium support or one of the 4 additional compendiums such as Lexi drugs and Micromedex drug decks. But most commonly NCCN compendium these, it's the one that goes off label more commonly than the others. But then don't stop there.

And I even encourage my payer colleagues on the managed care side to not stop there because the data changes too fast in oncology for payers to even keep up with. That's why payers can't rely on only FDA indications and NCCN compendium because something could get published in scientific literature tomorrow and now that's the latest greatest thing for our cancer patients. And we can leverage scientific literature. There are certain requirements per Centers for Medicare & Medicaid Services (CMS) for your Medicare members and then commercial and Medicaid typically follow suit, but there's certain requirements to secure off-label coverage of therapy and it typically has to be one of CMS's supported 26 journals.

So just to kind of pull in my bag of tricks, if you look at the ATHENA-MONO trial that was published in full text in the Journal of Clinical Oncology by [Bradley] Monk and colleagues that looked at the first-line maintenance use of rucaparib, which is not currently FDA approved today in that space. An SNDA has been filed but not approved, not listed within NCCN compendium to my knowledge. But because that study was published in full text in the Journal of Clinical Oncology and demonstrated a significant progression-free survival benefit even in the intention to treat patient population, biomarker agnostic, well that journal publication can supply insurance coverage and suffice for Medicare requirements typically for patients across the US and Puerto Rico.

Now there's always nuances but knowing your resources such as that and how to leverage scientific literature to gain access to therapy sooner can reduce barriers for you all even on the clinical side. So you don't have to have your patients go through denials and go through appeals and then that whole rigmarole that nobody even likes on the payer's side. And imagine what the patient might feel if they get a denial. It's horrible. So that's where payers need to know their resources, use scientific literature for coverage. That's the best trick I got in my bag.

Dr Joseph: That's awesome. And I think from what you said and what Dr Moore said, I think it's basically kind of knowing the patient's overall plan from the beginning. So I think one thing that I try to do in my teams is from the time the patient has their tumor debulking surgery, I'm like, okay, so what's the long term plan here? Are we going to try to do PARP or are we not doing anything? And if they say yes, PARP, then I kind of start the process sooner rather than later. That way if we do have to do appeals or prior authorizations or seek patient assistance, we have enough time. And it's not giving that patient the stress of like, Oh my goodness, I haven't started yet. You told me I needed to start 6 weeks after chemo. It's been 7. So I think that is great to know that we do have those resources.

Dr Bobolts: Absolutely.

Dr Moore: I did not know about the approved CMS list of journals. That is definitely going into my toolkit.

Dr Bobolts: I got you. No problem.

Dr Moore: Evidence for accessing drugs. So yes, I'm like, well, there you go. I didn't know that.

Dr Joseph: Does anyone have any last-minute comments or anything to add to today's discussion?

Dr Moore: Yeah, I think it's really helpful just to keep talking about the patient side of what we do and what our patients face. And also I think what our providers who aren't necessarily in big academic centers face. And I'm particularly mindful that most women with ovarian cancer are treated by very skilled medical oncologists who are in community settings where they do clinical trials and awesome things. And some of them are very large centers, but others are not. And so at my center, which is an academic center, I'm very blessed to have clinical pharmacists. So, after I finish counseling someone about anything, including a PARP, Dr Sarah Hayward walks in the room and spends another 45 minutes with them and they are fully counseled. So, it's a gold mine.

And then she's their first line of defense when they have problems and she handles like 95% of the calls right away. Patients get their questions answered, a mitigation strategy, and then a follow-up. That's amazing support that I have. And a lot of providers don't have that, financial counselors. I don't practice in a wealthy state. My patients cannot even have a $200 to $300 copay every month. And that is a choice for a lot of them. We have a lot of food insecurity in my state, staggeringly high rates. It's embarrassing in the United States that we have this, but we do. And so I can't put my patients at risk for further food insecurity to pay $300 a month for a PARP inhibitor. And so we have very aggressive financial counselors and my clinical pharmacists to really fight to get these drugs paid for, and if not paid for, replaced. And that's really an option when you are taking care of folks who are not incredibly financially well off.

It's harder when you have someone that's kind of working middle class or even upper middle class. Those tricks for getting high copays alleviated are harder actually there. And then they really do have a burden. $1000 a month for something? That's not doable even when you have 2 jobs sometimes and kids and all those things. So having financial counselors and all of this staff around to help my patients navigate financial toxicity, distance disparities, all the things help our patients stay on therapies. But when I think about other practices where they just don't have these layers of support, it gets daunting to help your patients stay on. Honestly, I wonder how they do it, in awe that they can honestly. Because I'm super spoiled, but my being spoiled means my patients have access to things. So I think it just speaks to how different practices are and how under-resourced a lot of our practices are for a lot of these things that our patients need.

Dr Bobolts: Very important. And I would just add from the managed care perspective, we're evolving always on the managed care side. And 2 ways in which we're evolving, and the first way you may be familiar with and the second way is very new. The first way is doing electronic prior authorization, but not just stopping at one division handles medical benefit drugs, which are typically your injectables, and one handles the pharmacy benefit drugs, which are typically your orals, like PARP inhibitors. But bringing that all together and making it 1 prior authorization done electronically, medical benefits and pharmacy benefits together.

So your bevacizumab and olaparib per the PAOLA-1 trial, taking a look at that entire regimen, but leveraging prior auth to be a second set of eyes on the patient's care in case they don't have services like you have, Dr Moore, that are amazing. Maybe they are in the community. And all of these PARP inhibitors, some per biomarkers, some not, can be confusing for people. So here, leveraging prior auth to be a second set of eyes and using oncologists to look at the prior auth and having oncologist to oncologist discussions and being like, perhaps that's not the right regimen per the patient's biomarkers, but this is what is the right regimen. So instead of denying therapy, offering an alternative.

So that's one way to modernize the older school. Some may call it dinosaur, but I think it can do so much good today prior authorization because it can do good when you leverage it as a second opinion. But now the second way is where we're going is this whole digital telehealth world. COVID has pushed us into this and it is actually opening fantastic doors for patients to gain access to clinicians, whether you're close to a large cancer center or you're in a rural area.

Right now, we have a digital telehealth solution for cancer patients where they can access our oncology nurses, our board-certified oncology pharmacists, our oncologists, in between their visits. More or less symptom management, late at night in the comfort of their home, on their phone they can access our clinicians to ask a quick question about how they're feeling with the side effects. We also treat mind, body, and soul because cancer affects everything. So within that tool, there's also unlimited mental health counselors that are available on the drop of a dime to do a Zoom visit with the patient. And in addition to hooking the patient up with a peer mentor, a cancer survivor, who's been through what they've been through, and that's really the way that we're revolutionizing managed care going forward.

Dr Joseph: That's amazing. That sounds great. And I know from experience that that's all there. Because I'll have patients say like, "Oh, I wasn't feeling well, but I called. They were able to put me through to a nurse and she told me to do this, this, and this. Do you guys agree?" It's kind of nice to know that all those resources are available and I think spreading the word is the most important part, is letting people know that they're there.

Thank you, Dr Moore. Thank you, Laura. This has been a great discussion and thank you all for joining us for our program today.

This transcript has been edited for style and clarity.