Managing Adverse Events from PARP Inhibitors in Ovarian Cancer
Clinical insights on how to manage adverse events for patients with ovarian cancer who are receiving PARP inhibitors.
Case: A 55-Year-Old Woman with BRCA-Mutated Ovarian Cancer
- A 55-year-old presents to her PCP for heartburn and abdominal pain that started approximately 2 years earlier.
- Imaging: Transvaginal US showed bilateral ovarian masses; CT reveals masses in adnexa, largest measuring 5.8 cm, with evidence of liver capsule and retroperitoneal lymph node involvement.
- Labs: CA125, 3600 U/mL
- Surgical intervention: She underwent hysterectomy, omentectomy, appendectomy, and debulking; residual disease was left on liver and diaphragm, approximately 2.2 cm
- Diagnosis: stage IIIc, high-grade serous ovarian cancer
- IHC testing: p53 (+)/ PAX 8 (+) /WTI and CK 7 (+)
- Germline testing: BRCA1 mutation
- Treatment: She received IV carboplatin/paclitaxel
- TRAEs: She experienced myelosuppression, most notably neutropenia (post cycle 3) that required postponement of next cycle
- Follow-up imaging: showed complete clinical remission after completion of chemotherapy; CA125, 30.5 U/mL
- Maintenance therapy with a PARPi was initiated.
- At week 3, her hemoglobin is 7.0 g/dL and she receives a transfusion
Transcript:
Leslie Randall, MD, MAS: The most common AEs [adverse events] with the PARP inhibitors are GI [gastrointestinal] toxicity, fatigue, and hematologic issues. GI [toxicity] is usually pretty easy to manage. Most of those patients will get used to the PARP inhibitor, and that will resolve within a month or so of starting. If you can get through that first month, you are usually in pretty good shape. It’s different from managing chemotherapy, nausea, because these patients are on therapy every day. It’s not like chemotherapy, where you have a cycle and they get treatment, they’re [nauseated] for 3or 4days, and then they’re fine for 3weeks. They’re probably going to have this every day. The good news, again, is that it typically gets much better within that first month, but if it doesn’t, we’re using things like medications that are easier to give longer term, like some low-dose olanzapine daily, instead of using the 5HT3 [receptor antagonists], which tend to add to the GI toxicity by causing a lot of constipation. Luckily, it resolves.
Fatigue is really interesting. If you look at fatigue, these patients have had surgery, they’ve had chemotherapy. They’re pretty fatigued after all that treatment, and if you look at all of the PARP [inhibitor] trials and look at the control groups, the fatigue rates are very high in the placebo groups. We try to rehab our patients. We try to give them physical therapy, support, exercise—nonpharmacologic ways of managing the fatigue. Fatigue can also be managed with dose modifications, as can GI toxicity. You don’t normally need to do this, but dose holds and dose reductions can help manage that fatigue. Sometimes the fatigue is due to anemia, which brings me to the [hematologic] toxicity. So for [hematologic] toxicity, we’re monitoring weekly CBCs [complete blood counts] for at least the first month or until that dose is stable, and we may have to adjust the dose in response to any of the cell lines, white count, hemoglobin, [or] platelet count. Once we get on a stable dose, [where it is administered] weekly until stable, then we’re monitoring that monthly.
I struggle with transfusion. I used to be a little bit more liberal with transfusion, and then it went away during [the COVID-19 pandemic]. We had blood shortages. We’re forced to manage these patients without transfusions, and I have more patients now in iron therapy, and even a darbepoetin [alfa] or another red cell–stimulating factor. You can use transfusion. You can also use dose holds and dose reductions to help manage the anemia. Anemias are pretty common, but interestingly, once you treat that first anemia in each individual patient, they tend not to have a recurrence. I’m not sure if I can explain that, but that tends to be my experience. If you have a patient who has all of their cell lines decreasing, that’s when you have to be vigilant and concerned about MDS [myelodysplastic syndromes][and] AML [acute myeloid leukemia], which is a class effect for PARP inhibitors. The earlier in their disease journey that you give the PARP inhibitor, the lower the rate of MDS/AML. In the frontline setting, about 1%. In the later lines, up to 8%. MDS/AML are observed in the control arms of all of the PARP [inhibitor] trials. It’s not totally a PARP [inhibitor] class effect, but it’s clearly a potential [adverse event] for a patient on a PARP inhibitor, and you have to watch for that.
The individualized starting dose of niraparib was helpful to help manage the toxicity associated with niraparib. It’s an important drug in our arsenal. We talked about how it’s the only one that’s available for the [patients with] HR [homologous recombinant]-proficient [cancers]. Early in the development of niraparib, very profound high-grade, prolonged thrombocytopenias were an issue with the drug administration. It was such an issue that we went back and looked at, what are the predictors of this significant thrombocytopenia? What we found was that a platelet count less than 100,000 or a weight less than 77 kg was predictive. Knowing that, you can apply that to the starting dose. For patients who meet either of those criteria, under [100,000 platelet count] at start or under 77 kg, you would start them at 200 mg daily instead of the starting dose of 300 mg daily. That makes a significant difference in the incidence and the grade of thrombocytopenia and the duration of thrombocytopenia when it does happen. That’s been helpful. In both our retrospective looks back at efficacy by the dose, it does not appear to affect the efficacy. Have we ever done an adequately powered randomized trial of 200 [mg dose] versus 300 [mg dose]? No, we’ve never done that. However, we do have a pretty large data set at this point looking at efficacy between the two doses, even at the 100 [mg] dose if patients require reduction to that level, and it does not appear to affect the efficacy.
Transcript edited for clarity.
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