Managing Patients Treated With PARP Inhibitors

Kathleen Moore, MD:As we move into an era where we’re using PARP [poly ADP ribose polymerase] inhibitors either as maintenance or in place of chemotherapy, understanding the adverse event profile of these assets is incredibly important. The studies will tell us that patients actually tolerate PARP inhibitors across the board very well, but they do require active management of frequent but low-grade toxicities to help patients feel good and maintain dosing for a long period. So, really paying attention and having an educated office. This isn’t something for which you can just give a bottle of pills and tell them you’ll see them in a month. Active management of the common things—fatigue, nausea, dyspepsia—are incredibly important in helping patients stay on study.

One of the essential things to keep an eye on with PARP inhibitors is the hematologic toxicity. For all 3 agents—olaparib, rucaparib, and niraparib—anemia is the most common adverse effect that we see. The grade 3 rate across the board is 20% to 25%, and of those patients, approximately two-thirds end up getting a transfusion at some point. And so, those adverse effects are managed by transfusions, and sometimes dose interruptions. And then, occasionally, dose modifications are required to keep patients on study. But it tends to be a very manageable hematologic toxicity.

Otherwise, across all 3 agents, and we now have data from the PRIMA study, which was frontline niraparib, the rates of grade 3 thrombocytopenia and neutropenia are really fairly low. The rate is less than 6% to 7% for neutropenia and around the same for thrombocytopenia. It is a bit higher for niraparib, at 13% on PRIMA. When niraparib first rolled out, it rolled out the flat dose of 300 mg, and it’s only once-daily dosing in a very potent PARP inhibitor.

What we learned over time is that not every patient likely needs that much. We did see much higher rates of grade 3 and 4 thrombocytopenia at the 300 mg dose level. It resulted in bringing down the dose to 200 mg in about 80% of patients, and for some, even to 100 mg. Something called the RADAR [rapid adjustment of dose to reduce adverse reactions] analysis was done of the NOVA study, which identified patients at risk. Those patients have baseline platelets that are less than 150,000, or their weight is less than 77 kilograms. So if they have either of those criteria, they’re at risk for significant thrombocytopenia and should be started at 200 mg instead of 300 mg. If they have neither of those risk factors, their risk of severe thrombocytopenia is about 13%.

So it’s a bit different than the other PARPs, but very manageable with what we call the weight and plates dosing.

Again, that came from the NOVA study. As soon as that result came out, the sponsor amended the ongoing PRIMA study to incorporate this individualized dosing for a patient. That data were presented at the Society of Gynecologic Oncology meeting in 2019, looking at the pre- and post-amendment hematologic toxicities, and you can compare it to SOLO1 because it’s frontline data. They’re very similar. There is still a bit more thrombocytopenia, but not a tremendous amount, and certainly a vast improvement over what was seen before. So the individualized dosing would appear to make the hematologic toxicities relatively similar across the 3 drugs.

The key piece of data that’s missing, of course, is the efficacy data from PRIMA, which hopefully will confirm that the individualized dosing did not impact efficacy, which quite frankly, none of us think that it will. But that’s really a key piece and will solidify individualized dosing for niraparib as the standard of care for maintaining safety and the ability of patients to remain on study and benefit.

Transcript edited for clarity.

Case: A 58-Year-Old Female With Heavily Pretreated Recurrent Ovarian Cancer

H & P

• 58-year-old female diagnosed in 2014 with stage IV ovarian cancer
  • Pathology: high-grade serous carcinoma, epithelial ovarian cancer
  • CA-125: 460 U/mL
  • CT with contrast of the pelvis, abdomen, and chest revealed a 4-cm mass in the left ovary and peritoneal carcinomatosis
  • Patient underwent suboptimal debulking surgery; residual disease 1.5 cm
  • Received IV/IP carboplatin/paclitaxel (6 cycles); achieved complete remission
• 2 years later (2016) symptoms returned; CA 125, 255 U/mL; ECOG: 1
  • Received carboplatin/paclitaxel (6 cycles) and bevacizumab; achieved good partial remission; CA 125, 45 U/mL; continued on bevacizumab maintenance
• 1.5-years following second-line therapy (2017), again presented with symptoms; CA 125, 550 U/mL; ECOG: 0
  • Genetic testing;gBRCA1/2wild-type
  • Received carboplatin/gemcitabine (6 cycles); CA 125, 46 U/mL; achieved complete remission
• Currently:
  • CA 125, 620 U/mL
  • CT shows several small masses in the lung left lower lobe (largest is 3 cm)
  • ECOG: 0