Clinical Commentary: Managing Adverse Events From PARP Inhibitors in Advanced Ovarian Cancer

Adverse Events on PARP Inhibitors

It’s interesting [to me that] the 3 PARP inhibitors, [rucaparib, olaparib, and niraparib], seem to act a little differently on different myeloid lines. For example, with olaparib, there’s a lot of anemia, and it’s affecting that red blood cell myeloid stem line.¹ With niraparib, we see a lot more thrombocytopenia, whereas with rucaparib we’re seeing more liver function test [abnormalities] and leukopenia. It’s interesting to me that the 3 PARP inhibitors that theoretically work on the same pathway each have their own unique issue, and that’s important, because managing that is what drives some of the symptomatic toxicity.

You’re going to see a lot of neutropenia with niraparib, but in the combination of olaparib plus bevacizumab we don’t see as much.² Nausea is worse with olaparib, and it seems to have some type of GI [gastrointestinal] first-pass effect that’s worse. I don’t see a lot of vomiting, at least in my practice. It’s mainly nausea, and fatigue across the board is bad. But I think that fatigue is being driven by anemia. There is not much hypertension with olaparib, maybe a scant amount with niraparib, and by adding bevacizumab, we see it increases [Table^1-3].

GI toxicity, like nausea, [is also challenging], but the most challenging in my experience is thrombocytopenia. That has been difficult to manage because [transfusion] is a temporary fix. However, patients will push to stay on the PARP inhibitors because they’d rather take a pill than sit in an infusion center for a couple of hours every few weeks.

Deciding Which PARP Inhibitors to Use

One of the things I do is look at the patient and see how they did [with] platinum-based chemotherapy. For example, if somebody [didn’t respond well] and had bad liver toxicity, I would steer [them] away from rucaparib, because that’s going to [increase] the LFG profile. [In comparison], if somebody started with high-volume disease and had a high platelet [count], we see that because it’s an acute phase reactant, I might be more inclined to use niraparib because they must have disease volume there. I would probably not use niraparib [for] somebody who had profound carboplatin-induced thrombocytopenia.

Patients are different, but I would use olaparib instead. In somebody who is a little older, a little more prone to fatigue, I’m probably less likely to use olaparib. A lot of factors go into the decision about which inhibitor you’re going to use, but I think age is a big part of it.

Are patients going to be able to tolerate that toxicity? If you have a 52-year-old BRCA-positive patient with metastatic ovarian cancer, I’d probably be as aggressive as possible and treat through the niraparib toxicities. Whereas if I have an 82-year-old patient with cancer [who has] wild-type BRCA with more medical problems, I might proceed with olaparib. So I try to look at the patient [holistically] to make that decision.

If this is somebody who developed [a] platelet [count] of 80,000/μL on cycle 2 [on] day 1 of treatment after 1 cycle of chemotherapy, that would make me nervous. I would say cytopenias from that treatment are bad. Regarding the patient’s performance status, I look at that, particularly in an older patient. For example, should we be using PARP [inhibitors] in an 85-year-old who has multiple comorbidities? Sometimes getting them through chemotherapy is a win.

Financial toxicity [is also a consideration because] for some patients these drugs are not going to be completely covered by insurance. Quality of life overall is incredibly important. I have a patient who was on a PARP inhibitor who was nauseated every day, and she kept losing weight. She said, “I have no appetite. I want to throw up all the time.” Is that any way to live? But there are some ways we can work with that, and we talked about decreasing the dose and about timing of medication. These are vital conversations to have with your patients.

Managing Toxicities From PARP Inhibitors

[To avoid some toxicities we are seeing], individualized niraparib dosing in the maintenance setting is important. This is what we call our weights and platelets, [and it] gives you some options to get patients through that initial toxicity. If their baseline weight is greater than 77 kg and their platelet [count] is above 150,000/μL, we can start at 300 mg once daily. If [their baseline weight is less than 77 kg and their platelet count is below 150,000/μL], we want to start at a lower dose.

For maintenance treatment of patients with ovarian cancer, [they] should start on a regimen with niraparib no less than 12 weeks after their most platinum-containing chemotherapy regimen. Then [make] dose adjustments for those AEs from niraparib. You want to go down; that’s your first dose reduction. You go down to 100 [mg]. At 100 [mg], you have to think about benefit analysis. For olaparib at 300 [mg twice a day], [reduce to] 250 [mg], then 200 [mg]. So for olaparib, it’s a [50-mg reduction]. The reduction for niraparib is a 100-mg reduction. Those are things to keep in mind.

Checking for Homologous Recombination Deficiency (HRD) Status

The only approved test is the Myriad my Choice HRD test. That is a true HRD score, and that’s important to keep in mind.⁴ When we look for HRD, we’re looking at 3 components: the loss of heterozygosity, large-field translocations, and large-scale translocations, as well as the balance among them. That’s what Myriad uses, and they generate the score that determines whether the patient has HRD. We know enough about the genetics of ovarian cancer to know what is driving the HRD status is the loss of heterozygosity.

A lot of [individuals] will use loss of heterozygosity as a surrogate marker, and that’s what they did in [the] ARIEL3 [study] [NCT01968213] with rucaparib. They used that as their surrogate marker for HRD status.⁵ I think that’s reasonable, and I believe other companies are giving you a loss of heterozygosity score.

I have used PARP [inhibitor] therapy in patients who [have] HRD negativity. If they’ve had a complete response, if they have a normal [level of] CA125 [cancer antigen 125], if their posttreatment scan [result] is negative, I will have a discussion with them. We then go through the PRIMA study [NCT02655016] data, and we talk about the fact that most of these patients are going to [have recurring disease]. If we use it in the up-front setting, it may be difficult to get in the recurrent setting because an insurance company could say, “Well, you already used this.”⁶

There are some patients who want it, there are some patients who say, “I want to try everything now and keep this at bay,” and there’s a subset of patients who are going to keep the disease at bay in the up-front setting. I don’t use it in all patients. I use it in patients with BRCA in their cancer and almost all my patients [who have] HRD. That’s why that marker is so important.

Adding Bevacizumab to Treatment

Bevacizumab has a couple of roles to play in treatment. The first is in patients [with suboptimal cytoreduction], because we know in [the] subset of patients in the GOG-0218 [NCT00262847] and ICON7 [ISRCTN91273375] studies, those patients were the ones who benefited most.^7,8

Let’s say the patient had high-volume disease. We’re able to get most of it, but a decent amount was left behind for whatever reason. I’d probably add bevacizumab to the therapy. Another [patient for whom] I might consider adding bevacizumab is one with stage IV cancer. For example, I would add it [for] someone who had pleural effusion [or] disease in the lung or [for] someone with high-volume ascites, because it is therapeutic for that patient and dries up the ascites quickly. The trade-off, however, is the hypertension and [that a patient with] a [lot] of ascites probably has a fair amount of disease on their bowel.

It makes me a little nervous about giving bevacizumab to someone and then [seeing them have] a bowel perforation. But those are generally the patients [for whom] I will use [bevacizumab] in the up-front setting.

Dose Management

One thing we try to do, because we don’t want to lower the dose, have some nausea, and not get the benefit, concerns timing. So if they’re on 300 mg of niraparib, we may break that dose into 2.

If they’re on olaparib, we may space it out over the course of a day. We also tend to use some degree of schedule for antinausea medications, even though that can make patients a little foggy. Salty foods can also help a little around the time of treatment because they take a little edge off. So there are little things you can do to help with chemotherapy-induced nausea.

It’s also reasonable to hold therapy, monitor the patient, and restart at a reduced dose [depending on how they react to treatment]. It’s not unreasonable to restart at the same dose, though you’ll probably get the same result. Sometimes patients need some time to acclimate, and it’s fine not to switch or discontinue therapies in this scenario.

_REFERENCES

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_{2. Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361}

_{3. Niraparib. Prescribing information. GSK; 2021. Accessed August 11, 2022. https://bit.ly/3QA5AGU}

_{4. Learn how an HRD test can help inform your treatment options. AstraZeneca. September 9, 2020. Accessed August 11, 2022. https://bit.ly/3zZjPia}

_{5. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. doi:10.1016/S0140-6736(17)32440-6}

_{6. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/ GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/ NEJMoa1910962}

_{7. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi:10.1056/NEJMoa1104390}

_{8. Oza AM, Cook AD, Pfisterer J, et al; ICON7 Trial Investigators. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomized trial. Lancet Oncol. 2015;16(8):928-936. doi:10.1016/ S1470-2045(15)00086-8}