Shahin Analyzes Benefits of Individualized Dosing With PARP Inhibitors in Advanced Ovarian Cancer

Mark S. Shahin, MD (MODERATOR)

Director, Hanjani Institute for Gynecologic Oncology

Abington Jefferson Hospital

Willow Grove, PA

CASE SUMMARY

At a virtual Case-Based Roundtable meeting, Mark S. Shahin, MD, led a conversation with his fellow oncologists on the use of PARP inhibitors as first-line maintenance therapy for patients with advanced ovarian cancer. They discussed how to decide on the best dose of niraparib (Zejula) for these patients and how the drug class impacts adverse event management. Further, Shahin looked at the future of the drug class for patients with ovarian cancer.

PARTICIPANT LIST Alexander Barsouk, MD | Lewis Rose, MD | Meher Burki, MD | Gabor Varadi, MD | Charlesse M. Pondt Huannou, MD | John Kosteva, MD

Event region: Pennsylvania

DISCUSSION QUESTION

• Why have you used or not used niraparib with an individualized starting dose?

SHAHIN: At the time you want to prescribe niraparib, if the patient’s body weight is [more than] 77 kg and the platelets are over 150,000/μL, then the starting dose can be kept at 300 mg.¹ However, if the patient weighs less than 77 kg or the platelet count is less than 150,000/μL, then a 200-mg dose is what’s recommended, which is how it was conducted in [the PRIMA study (NCT02655016)].¹ For those of you who have prescribed niraparib, what is your preferred way to start [this therapy]?

BARSOUK: I start [at approximately 300 mg] if the patient weighs [more than] 77 kg, then I’ll adjust the dose depending on how they tolerate it and the degree of [adverse events (AEs)]. If somebody weighs less than 77 kg, then I will start them at 200 mg.

ROSE: From now on, I’ll probably start at 200 mg because I‘ve had problems with [some] hypertension…and of course severe myelosuppression in some patients.

So I did start at 300 mg, but I think I’m a little gun-shy now and will probably start at 200 mg and work up [from there].

SHAHIN: To be honest with you, the main issue [is] that thrombocytopenia seems to be unacceptably high when we don’t observe this individualized dosing criteria. If you look at it using the individualized [starting dose], thrombocytopenia goes from 48% to 21%, anemia goes from 36% to 23%, and neutropenia goes from 24% to 15% [Figure²]. All [these data] point toward patients who are more [adherent]; they stay on the medication longer and have [fewer] treatment interruptions. I want to emphasize again that [using this strategy for] niraparib dosing for patients who were in the intent-to-treat population [of the phase 3 PRIMA study] demonstrated a median progression-free survival [PFS] of 24.8 months vs 8.3 months [in those without an individualized starting dose] and was significant [HR, 0.45; 95% CI, 0.34-0.60; P < .001].²

In the homologous recombination–deficient subgroup, it was remarkable in that the median PFS [was] not reached [compared with] 11.0 months in the placebo group [HR, 0.48; 95% CI, 0.34- 0.68]. Similar data can be seen in the [subgroup of patients with] germline BRCA-mutated disease, but [those without a germline] BRCA-mutation benefited at 19.3 months vs 8.3 months [HR, 0.48; 95% CI, 0.34-0.67]. So for those of you who are very much into dose density, I want to emphasize that individualized dosing [with niraparib was] beneficial to the patients.²

DISCUSSION QUESTIONS

• Which AEs do you observe most frequently when using a PARP inhibitor in the primary maintenance setting, and which are the most challenging?
• Do you notice any differences in tolerability in the primary maintenance setting vs the relapsed/refractory setting?

BURKI: In my experience, gastrointestinal toxicity and fatigue are the most common AEs that cause people to not continue the treatment.

SHAHIN: How do you handle that in your practice?

BURKI: With niraparib, for instance, I always start off with the 200-mg dose. I feel like that’s a more tolerable dose. I only dose escalate if I feel like the patient can tolerate it. I do the same thing with olaparib [Lynparza]. For the first 1 or 2 weeks, I tell them to start once a day [with the PARP inhibitor] and then build up the dose as they tolerate it. Then, like with olaparib, a lot of my patients are taking Zofran [ondansetron] half an hour before they take the medication. Things like that help them get through AEs.

SHAHIN: I think your approach is very valid. [Does] anybody else have any comments about AEs that you see and what you have done to overcome their challenges in your day-to-day practice?

VARADI: I wanted to ask you: How does myelodysplastic syndrome [MDS] change across [subgroups of these patients]?

SHAHIN: We have not [necessarily] seen a higher frequency of MDS in patients based on their homologous recombination status.² I think that’s what you’re asking, and I’m aware of that at the moment. I do agree that, across the board, this class of medications requires a lot of education up front. I do find that our nursing staff and allied staff spent a fair amount of time on the phone [and] in person with these patients [to treat AEs]. If you want to continue with them, many of these AEs appear to become more manageable as time goes on. And I want to recommend that weekly calls should be with the patients, especially during that first month [of treatment]. This is because early intervention is key.

KOSTEVA: So, mostly it’s just seeing cytopenias, nausea, or fatigue [when patients are on this class of drug]. Another AE that’s not [really] recorded is the financial toxicity that comes with a lot of these oral drugs. That can be a tough sell sometimes for patients, where they might have a higher out-of-pocket cost with maintenance PARP inhibitors, [such as] maintenance bevacizumab [Avastin].

ROSE: I had a patient who had grade 2 pneumonitis with olaparib, and she was insistent on going back on it, and now she’s still in remission. This was given in the second line for recurrence of platinum-sensitive disease, and she responded rapidly to steroids [to treat the AE].... With checkpoint inhibitors, we have clear-cut criteria for [the] management [of pneumonitis]...but there are no [current] clear-cut criteria for managing PARP inhibitor–induced pneumonitis. I don’t know [whether] there is in your experience. Also, in some of the patients [who] I’ve had on PARP inhibitors, almost all of them seem to have macrocytosis, even if they don’t develop severe myelosuppression. I don’t know [whether] that’s something that’s been seen as well.

SHAHIN: Pneumonitis is rare, and I…have come across 3 cases [of pneumonitis]. In all 3 cases, I’ve hesitated to go back to the PARP inhibitor ever again [for these patients]. As you mentioned, low-dose steroids for a short period of time resolved the problem, and none [of these cases of pneumonitis] became a permanent issue for the patient.

As far as the macrocytosis goes, I do find that if you run into patients who have significant anemia, then macrocytosis can be seen. I do give them breaks [from therapy], then I employ a dose reduction after that. With that strategy, I’ve been able to continue to keep the patient going [on treatment] and have not encountered significant problems. I think many of you are well versed in managing patients with cytopenias, and I would just encourage you to look for other causes. For instance, many of these patients have bowel resections. One of the [other] areas that we don’t pay attention to enough is...that many of these patients may have [unaddressed] vitamin deficiencies. Then for a persistent anemia problem, I recommend we tap into our hematology colleagues. Lastly, I want to say that you’re correct that further investigation [should be done], especially into specific causes of hematologic disorders associated with these agents. I’m somebody who wants to look beyond the weights and the platelet counts, and I want to know [whether] there are specific genomics that we should use to either not prescribe these agents or maybe dose reduce those patients. I haven’t come across anything that’s convincing or practice changing yet, [in this regard].

The one other question I wanted to ask you all is: In your experience, have you seen different tolerability in the primary maintenance vs refractory setting?

HUANNOU: I find that patients tend to tolerate—particularly succeed—[PARP inhibitor therapy] more often in the primary and maintenance treatment setting. Sometimes there’s a drive to make sure the disease doesn’t come back, which allows people to push through a lot of the AEs, whereas if they’re in the relapsed/refractory setting, I think the patient is a little more worn down sometimes and quickly want to move on [from treatment].

_REFERENCES

_{1. Zejula. Prescribing information. GSK; 2020. Accessed January 5, 2024. http://tinyurl.com/msubk4vc}

_{2. Li N, Zhu J, Yin R, et al. Treatment with niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2023;9(9):1230-1237. doi:10.1001/jamaoncol.2023.2283}