Part 1: Addressing Toxicities of PARP Inhibitors for Ovarian Cancer

Adam C. ElNaggar, MD (Moderator)

Gynecologic Oncologist

Oncology Medical Director

Natera

Memphis, TN

DISCUSSION QUESTIONS:

• What adverse events (AEs) do you observe most frequently when using a PARP inhibitor in the primary maintenance setting, and which are the most serious?​
• Have you noticed any toxicities you did not anticipate/were not reported in literature? ​
• Do you notice any difference(s) in tolerability in the primary maintenance setting versus the relapsed/refractory setting?​

ADAM C. ELNAGGAR, MD: So, what AEs do you observe most frequently when using a PARP inhibitor in the primary maintenance setting?

LOUAY HANNA, MD: Definitely with the olaparib [Lynparza], I see the hematological AEs and neutropenia more so than any other AEs.

ZUHAIR GHANEM, MD: I have good experience with these PARP inhibitors. Honestly, even if the patient has cytopenias, they are usually well managed, and I rarely have to stop or switch the treatment. Sometimes gastrointestinal issues could be a concern in some patients. Overall, I don’t recall a patient that I had to stop the treatment for AEs. They are well tolerated.

When I counsel the patient up front, I say it’s a well-tolerated treatment compared with the benefit. You’re giving a pill, the AEs are mostly minimal, and the patient has such a great benefit, especially in the patients with BRCA mutations.^1,2 So, I counsel them what to expect when they’re on the treatment, and what AEs we face. Most patients do fine on this treatment, which is better than when we were treating patients with bevacizumab [Avastin] or any other maintenance therapy.

JIGAR SHAH, MD: In my patients, 1 had pretty bad pneumonitis, and I also had a patient with a pulmonary embolism [PE] 3 to 4 months after initiation of therapy. So, those are rare but I also counsel the patient on those. These drugs, if given long enough, can be a risk factor for developing myelodysplastic syndrome down the road, so I counsel the patient on that before initiation of the therapy.

ELNAGGAR: That patient that had the PE, was that a bevacizumab/PARP inhibitor combination, or was that the PARP inhibitor alone?

SHAH: PARP inhibitor alone.

ELNAGGAR: And the pneumonitis, what did you do for that?

SHAH: We treated them with antibiotics initially, but they still were having symptoms, so I had to put them on steroids with concurrent anticoagulation, and they started to improve. So, I was lucky I didn’t lose the patient, but it was scary at one point, and symptoms were severe.

ELNAGGAR: Do you go back to a PARP inhibitor if somebody has that?

SHAH: I had to change the therapy, because the patient didn’t want to go back on the therapy.

ELNAGGAR: Would anybody put a patient back on a PARP inhibitor after pneumonitis?

WEI LIN, MD: I did not have a patient that had a PE or other severe hematologic toxicity; [but I had] 2 patients with gastrointestinal toxicity, and 1 patient felt that it was [too] difficult to keep going because of the diarrhea. It depends on the patient. If the patient is motivated, even the most [serious] AEs can be managed. Most of patients tolerate PARP inhibitors well, but some patients just don’t want to do it.

VENU MADHAV KONALA, MD: I managed most of the AEs with dose reduction. I had 1 patient who received 300 mg of olaparib twice a day who had had severe fatigue. I tried dose reduction and re-ramping it up, but she still had severe fatigue. Now she’s getting 200 mg twice a day. But most of the AEs are managed with dose reduction. With niraparib [Zejula], I saw thrombocytopenia with every patient I started on it. I have to dose reduce.

ELNAGGAR: We’ve had the PARP inhibitor indications for a few years now for second- and third-line therapy, definitely longer than we’ve had the frontline indication.^3,4 We probably got experience doing that in the recurrent setting. Did you notice anything different when you started doing it in the front line? Toxicities, or tolerability, anything like that?

KONALA: I only had 2 patients where I used it in second and third-line settings, but I didn’t notice much difference, apart from the hematological toxicities, which I felt were [slightly higher in the first line].

MICHAEL HEMPHILL, MD: I haven’t [seen a difference] so far. Our group has some gynecologic oncologists who manage more of the patients with ovarian cancer. I [only] have a few. So, some of my experience with PARP inhibitors is from trials for other cancer types. And thus far, with both [olaparib and niraparib], I feel like the toxicity profile’s been pretty good, mostly [AES related to] blood counts. I saw some headaches as well; I forget which 1 of the 2 [PARP inhibitors were used]. But by and large, I think it’s incredibly well tolerated, at least in my experience so far.

ELNAGGAR: I would agree with that. But for the PARP inhibitors, I haven’t seen much of a difference in terms of whether they have toxicity, whether they tolerate it, what to do to manage it; I’ve seen it be pretty much the same, too.

_References:

_{1. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962}

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

_{3. Olaparib (Lynparza). Prescribing information. AstraZeneca Pharmaceuticals; 2021. Accessed February 24, 2022. https://bit.ly/3LXfkJQ}

_{4. Niraparib (Zejula). Prescribing information. GlaxoSmithKline; 2021. Accessed February 24, 2022. https://bit.ly/3LUC2Cu}