Assessing the Challenges and Advantages of PARP Inhibitors as Maintenance Therapy in Advanced Ovarian Cancer

David M. O’Malley, MD (MODERATOR)

The Ohio State University Wexner Medical Center

The James Comprehensive Cancer Center

EVENT REGION California, Nevada, and Arizona

PARTICIPANT LIST Ike Onwere, MD | Aneel Chowdhary, MD | Elaine Beed, MD | Ming Yin, MD | Arun Kumar, MD | Arun Sendilnathan, MD | Ilia Buhtoiarov, MD

CASE SUMMARY

A 49-year-old woman presented to her primary care physician with abdominal bloating and nausea. She had a prior medical history of mild hypertension and a family history of cancer. Her mother died of breast cancer at age 59, and a cousin on her mother’s side died of ovarian cancer at age 65. The CT scan showed small-volume ascites and bilateral 8-cm adnexal masses. Cancer antigen 125 levels were 285 U/mL, and she underwent exploratory laparotomy, followed by omentectomy, bilateral salpingo-oophorectomy, and resection of peritoneal nodules for stage IIIC high-grade serous carcinoma. There was an optimal cytoreduction, with less than 1 cm of residual disease after surgery.

DISCUSSION QUESTION

• How do you counsel your patients about PARP inhibitor use in the primary maintenance setting? What factors do you address?

ONWERE: When our patients think of getting oral chemotherapy, they often think that the therapy would be much easier. For most patients who I’ve had on PARP therapy, the main issues are often fatigue and [gastrointestinal] symptoms, so it isn’t an easy therapy to give. But after the first 3 months [of treatment], most of those symptoms typically improve.

O’MALLEY: I think you’ve hit on the 2 most important points. Patients say, at least in gynecology, “Oh, it’s a pill, great!” Well, yes and no. It’s chemotherapy every day rather than once every 2 or 3 weeks. The second thing is the tolerance, which is interesting. I thought it was made up when I first started hearing, “If you can get them through the first 3 months, it seems to be much better tolerated.” Well, you dose reduce; that’s why [we can help patients through treatment]. But there is something real with regards to getting patients through those first couple months and seeing how they’re doing from a tolerance standpoint…. [Approximately] half the patients will need a dose reduction if you start [with the] full dose, and we need a lot of work to get them through those first couple months.¹ We send our patients home with antiemetics, or they’ll have them at home because they just came off carboplatin plus paclitaxel. There are different ways to go about it. Also, [we need] education for the nursing team to make sure we’re keeping on top of [any toxicities]. [Are there] any other comments on some of the challenges or questions you may have?

CHOWDHARY: I have to say that when we’re talking to patients, especially in these settings where you’re looking at their BRCA and [hormone receptor] status as well, it’s a complicated [treatment algorithm to describe]. I usually open up the National Comprehensive Cancer Network guidelines as well…but in the end, when you’re looking at the maintenance phase, the discussion revolves around goals of care and the toxicities expected. As alluded to earlier, I found fatigue and [gastrointestinal] symptoms to be the biggest issues I see. I’ve done more dose reductions [of a PARP inhibitor] due to fatigue, probably even more so than gastrointestinal issues. I’ve primarily used olaparib [Lynparza] and rucaparib [Rubraca] for these patients. With rucaparib, I’ve noticed I’ve had to dose reduce slightly more. But I agree, after 3 to 4 months, [patients] seem to be on an even keel. For the goals of therapy, I do tell [the patient] that we’re looking at survival benefit. It is palliative, but we’re trying to suppress the disease for as long as possible. But we’re looking at better survival, too.

O’MALLEY: I’m going to push back a little bit about whether we are curing patients…. In [treating patients with] advanced ovarian cancer, we need to change the dialogue to: “We’re going to help increase the chance of curing you.” I know that’s a word oncologists don’t talk about in advanced stage, but I think we need to [now].

DISCUSSION QUESTION

• What adverse events do you observe most frequently when using a PARP inhibitor in the primary maintenance setting? Which are the most challenging?

BEED: What I see [the most] is diarrhea.

O’MALLEY: Interesting. [That’s] not as common, but diarrhea can be a problem.² What’s interesting is you often see the nausea with the diarrhea, so the antiemetics can help take care of [both]. I’ve only had a couple patients where it became a problem, but yes, some gastrointestinal upset [was still seen]. For the antiemetics, I use a lot of ondansetron [Zofran], and that sometimes [takes care of both issues].

YIN: For me, the major challenge is bone marrow suppression. Of course, over time, the [patient could] have neutropenia and thrombocytopenia. I have some patients who had a range of less than 20,000 platelets/μL of blood, and you must pause the treatment. Of course, this is in the first-line setting, but the relapsed setting also creates a challenge for patients who need salvage chemotherapy.

O’MALLEY: The hematologic toxicity, particularly in the recurrent setting, is real, [and] particularly from anemia. Typically, I used to…keep treating through, but now I dose interrupt, transfuse, and I would restart them with the same dose overall. I [just] do a lot more dose reduction now. But I’m curious, do you see more issues with hematologic toxicity in patients who had previous radiation?

YIN: It depends on the site of the radiation. If it’s to the pelvic bones, it will create a problem. But if it’s, for example, the rib bones—so not bone marrow–enriched areas—it should be OK.

O’MALLEY: Yes, I see some differences. We don’t use much radiation in ovarian cancer, so it’s not something I have to deal with. I was wondering [whether] that potentially was an issue.

KUMAR: In general, fatigue and cytopenia are the most common.

SENDILNATHAN: I have experience using niraparib [Zejula] and olaparib. Niraparib caused severe thrombocytopenia that lasted for weeks to months. I remember this was [a patient who was] 50 to 55 years old who had single-digit thrombocytopenia [that] recurred even after dose reduction, so I had to stop it and switch her to olaparib. When I switched her to olaparib—and because the approval is for olaparib plus bevacizumab [Avastin]³—using bevacizumab was problematic with that regimen because she was already thrombocytopenic and continued to be more thrombocytopenic, so I was worried about any bleeding in her.

O’MALLEY: Wow, that’s interesting about the bevacizumab. From a hematologic standpoint, with niraparib, one must use the patients’ weight and platelet count. And yes, you dose reduce to 100 mg/day.⁴ I’ve had it both ways; I’ve had hematologic toxicities and I’ve had to switch from niraparib to olaparib. I’ve also had weird adverse effects like fatigue because of the twice-a-day dosing, so for [patients] who are struggling, I’ll switch from olaparib to niraparib. No data support that, but trial and error and seeing—particularly in some of our subpopulations like homologous recombination deficiency, BRCA, RAD51C, or RAD51D positive—these patients are just so clearly going to benefit. Again, we don’t have much BRIP [or] BARD, but I know we’re seeing some exciting results across other tumor types there.

DISCUSSION QUESTION

• When are you doing your somatic and germline testing? Are you doing both at the same time?

CHOWDHARY: At our institution, we do pretty much both at the same time up front. It’s automatic once they have an ovarian cancer diagnosis, then we reflexively get the next-generation sequencing [NGS] panel. But then they are referred to genetics for germline testing pretty much at the same time. I think that’s how we’re approaching this.

O’MALLEY: So, its hardwired [that] if they get that diagnosis, they’re going right for that testing?

CHOWDHARY: Yes, I think it’s more institutionalized.

O’MALLEY: If we can make [testing] simple and brainless for us with busy practices, that’s good. Other practices?

BUHTOIAROV: At Cleveland Clinic, it’s also automatic up front as soon as we have the diagnosis. All this testing gets unfolded so that we have the results probably within 2.5 weeks.

ONWERE: How often would you get an NGS panel that’s negative and have a positive germline test?

O’MALLEY: The way I’m taking your question is that you use the somatic test results as a reflex to germline testing, which a lot of people are doing. It’s interesting. I’ve been working with my genetic counselor and I looked at the data, and with large deletions or rearrangements, you could miss them on somatic testing. So, what is that number? I’ve heard 7%, but is that 7% vs the overall occurrence of positivity? It’s not a real 7%. You’d expect for patients with ovarian cancer [to have the] BRCA gene, [and then it may mutate]. When we look at that, there’s 2 reasons why I do what I heard others say, which is both tests at the same time.

One of the big reasons is I don’t want to miss those large rearrangements or deletions. The most important reason is when I sit down and tell that patient she has a BRCA on her somatic test, the first question they ask is: “Is my family at risk?” So, I immediately want to be able to say [whether] this is germline. Because, again, if we take [approximately] 15% to 20% who have germline, another [approximately] 10% to 15% will be only somatic. So, for me, if I have that group of patients, I want to be able to tell them immediately, but I do worry about missing them. We do so much testing for 1% to 2% to miss something that could be as high as another 7% vs our baseline. I don’t think it’s wrong. I have a lot of friends around the country who do somatic and then reflex, but I personally would want to have the germline in BRCA. I started even doing it in uterine cancer because we’re picking up a lot for patients who have advanced or metastatic disease or high-risk type.

_REFERENCES

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_{Liu Y, Meng J, Wang G. Risk of selected gastrointestinal toxicities associated with poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of ovarian cancer: a meta-analysis of published trials. Drug Des Devel Ther. 2018;12:3013- 3019. doi:10.2147/DDDT.S164553}

_{FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. News release. FDA. May 8, 2020. Updated May 11, 2020. Accessed September 21, 2023. https://tinyurl.com/yjd7bhzu}

_{Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792. doi:10.1093/ annonc/mdy181}