Ovarian Cancer: PARP Dosing and Future Outlook

Thomas Krivak, MD:Those are 2 really important abstracts looking at a dosing of niraparib, because when we think of oral agents, I think a lot of us clinicians, as well as patients, thought an oral agent—it’s not going to have the same adverse effects, or there are adverse effects we won’t have to worry about like we did for chemotherapy, and that’s not true. Niraparib has done a fantastic job of going from phase I to phase III, and it’s a very exciting compound with how it’s excreted by carboxylesterase. It has high bioavailability, good tissue penetration. To me, all that is very exciting to treat tumors. At one point, you know, you had to worry about the adverse effects—fatigue, nausea, vomiting—as well as thrombocytopenia.

Looking at the weight-based dosing and looking at the criteria that they use to look at the patient’s baseline weight, as well as baseline platelets, I have to be honest with you: I think if—when we use those criteria, about 70% of patients at our clinic are going to get dosed at that lower dose at about 200 Q day—that if you talked with nurses, myself, the PAs [physician assistants], and the patients…I think the number of adverse effects that decreased—the thrombocytopenia has decreased, the fatigue has decreased, some of the, some of the nausea’s decreased.

In general—when we start somebody on PARPs, in general in niraparib, we’ll tell them to take it at night, we’ll give them prescriptions to help with diarrhea, prescriptions to help with constipation, as well as nausea and vomiting. I’ve heard some people are trying to use just some baseline antiemetics consistently for about 2 months to not let the cycle develop. I typically haven’t done that because I think taking it at night will help with that, and then treat those patients as needed. I’ve used some low-dose steroid. I put a patient on low-dose steroids for like 2 weeks, and that really helped her nausea, and she’s been doing fine after that.

I think there are many different ways that we can try to tweak that. I would say that starting at the lower dose, we’ve seen the decrease in the adverse effects. It’s hard to say. You know we want to make sure that everything stays as effective. We haven’t seen any patients that had seemed like they’ve had a rapid falloff with respect to recurrence or anything other than what we’ve seen within the literature.

It’s something that we need to pay attention to. The FDA dose is 300 down to 200. There are many drugs that I would have to say that we use in GYN [gynecologic] oncology that the FDA dose may be higher than what’s the typical dose that we use when we treat patients. But, to me, niraparib—using the weight-based dose, the individualized dose—I think, you know, I await the FDA’s review of that to see if they’re going to approve that. I think in clinical practice—so, phase IV data—using the drug in clinical practice, it has definitely borne out, and it was definitely very helpful. So the abstracts by—I think it was

We have a lot of interesting single-agent compounds that we’re now starting to do the combinations. I mentioned TOPACIO; I think that’s the tip of the iceberg, that we’re going to do many of these types of combination therapies. I also think that the amount of molecular data that we’re going to need to interpret when we see these patients is going to become more complex. I also think that we’re in the era of 5% medicine, which means, you know, we may have to send off 20 tests to find 1 test [so] that we can make a significant change in therapy that may make a significant change in outcome.

I think that the next 5 years are going to be very exciting, just like these past 5 years. We have other drugs. Hopefully, they’ll be coming out with some antibody-drug conjugates, combinations of many of these therapies. The first trial, which is combination Avastin, dostarlimab(?), as well as niraparib—an up-front setting for maintenance therapy, I think, is going to be a very important trial, because we talked about BRCA, we talked about HRD [homologous recombination deficiency]. Unfortunately, most patients are HRD negative, and that’s where we’re struggling right now with our treatment, so as we can come up with better combinations…

I do think that combination immunotherapy with PARP inhibition is going to be very important. I look forward to the dostarlimab data with niraparib. There [are] other trials being done out there that are going to be looking at that from Clovis as well as AstraZeneca. All these companies, I think, are benefiting our patients with the rapid drug development and the development of these combinations, which is a huge change compared to 10 years ago. We have so many clinical trials available for patients; the change is rapid, which is excellent for them.

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