Recurrent Ovarian Cancer: QUADRA Trial

Thomas Krivak, MD:I think the QUADRA Trial was really important in that it had 460-some-odd patients that were heavily pretreated. What I think we were trying to do with the QUADRA data is…we had development of PARPs, which started in treatment of patients who hadBRCA-mutated tumors, it was germline, and then expanded into germline and somatic BRCA treatment. Then we kind of switched, and we had all the good data coming out with maintenance therapy.

There was this gap—can we use PARP inhibition in all-comers? QUADRA looked at all-comers, and then they kind of took out some data points looking at patients who hadBRCAmutations and patients who had HRD [homologous recombination deficiencies] genomic scaring, and then all-comers. Really, what they did is, when they looked at it and they saw the patients who hadBRCAmutations treated at fourth line or greater, they had excellent response rates for platinum sensitive, platinum resistant, as well as platinum refractory. They had really good response rates in all-comers withBRCA 1orBRCA 2mutations, and then again when expanding the indication using HRD in patients who had the HRD genomic scar, but not aBRCAmutation, and those patients who were platinum eligible, those patients had durable responses, as well, with respect to having PARP inhibition at that time.

I think these data are definitely practice changing. What it does is, it’s taken our portfolio of PARP inhibitors where we should use them and expanded it to additional therapy and then expanded it to HRD. Again, the label is fourth-line therapy or longer. If you had a patient who came in at second- or third-line, she had aBRCAmutation, platinum-sensitive recurrence, this is somebody who said, “Tom, I drive an hour and a half from West Virginia. I really do not want to be driving back and forth for chemotherapy. It’s something that I would prefer.” Sometimes their co-pays may be higher for the chair time and, so, the oral agent.

I used the PARP inhibitor on a patient who couldn’t make the drive, and she just wanted to come in once a month for labs, and she thought that that was a better way to go. There were many clinical trials at that time looking at this. I think the QUADRA data are practice changing in that they show that it’s expanding the indication. They show that you can use it in heavily pretreated patients because in the QUADRA trial, there was a significant portion of these patients who had 6 lines or greater. To say somebody’s had fourth-line, fifth-line therapy, we shouldn’t use PARP inhibitors—niraparib has shown that you can use that at the 6-line treatment for these patients. I think it’s been a nice addition to a portfolio that gives us choices and options to give to patients when we’re sitting down talking with them in, in the clinic.

I think that, looking at the data…using a biomarker in this heavily pretreated patient group is appropriate. Do I think that if they would have used it in less pretreated patients, would they have had different responses? I think anybody would say yes as we move these drugs up in drug development. I think that this met an unmet need. This is something that we’re starting to see more often, in that patients are living longer; we’re having to figure out what can we give them for fourth-, fifth-, sixth-line therapy. I think that’s a very nice addition.

I also think that it’s looking at molecular signals. We have to pay attention. Is the patientBRCApositive? Did we have this HRD test? I think it’s really trying to take the biomarker and apply it to the patient even further down the line when most of us would say at fifth-line therapy or sixth-line therapy, the chance of response is 5% to 10%. When you’re looking at the response rates in QUADRA, they’re much higher than that, especially for BRCA in the 40%, 30% range. To me, those are pretty remarkable response rates.

I kind of, you know, quoted some of the TOPACIO data, which I think are very important; combination niraparib with IO [immuno-oncology], getting a good disease control rate in a very challenging group of patients to treat. I think that those are very good studies done by Tesaro/GSK [GlaxoSmithKline], which has given us options to talk about with our patients. The more options we have for our patients, that means the more treatment that we could, hopefully, give them later on.

So, I think in the platinum-resistant or platinum-not-eligible patients, in the QUADRA trial, they looked at BRCA. So you had to have aBRCA1or2, germline or somatic mutation. And I agree with that. I think if you have that, you should be able to use single-agent niraparib. I would also say that if you didn’t have those mutations and you didn’t have the HRD—because in the platinum-ineligible or platinum-resistant patient, that’s when they would use the HRD tests. So, HRD-positive test, platinum—you had to be platinum sensitive. But if you had the HRD test and you’re platinum insensitive, it’s not an indication. I would take those patients and I would say that it’s not that single-agent niraparib cannot be used. It didn’t bear out in the QUADRA data, but what I would say is, take the TOPACIO data, which is combination niraparib and immunotherapy; use that combination for those folks at that time, because I think that would get you a good disease control. Because when you look at that trial, those patients were heavily pretreated_,as well.

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