PARP Inhibitors in Advanced Ovarian Cancer

Kathleen Moore, MD:As evidenced by the historical case we’ve discussed and the discussion of the changes in the standard of care, there are several big questions coming up and we’ve alluded to some of them. We’ve got studies in the platinum-sensitive maintenance setting with PARP [poly ADP ribose polymerase]. Now we’re entering a world where many patients will receive a PARP inhibitor in the frontline, so a big question is going to be the use of PARP after PARP. We don’t have answers to that today, but that’s 1 of the big questions facing our field.

One of the other big questions that we probably will have answers to before the PARP after PARP question is, can we substitute? Do we have enough evidence to substitute PARP inhibitors for chemotherapy, either as monotherapy or in combination, to really continue to help our patients live longer and have what may be superior adverse effect profiles and better quality of life off of systemic chemotherapy? As I’ve alluded to in the past, the single-arm phase 2 trials that are available with rucaparib in ARIEL2 and Study 10 data, and olaparib and the Dr Bella Kaufman paper. When you think about monotherapies, the PARP inhibitor, the largest study to date, single-arm study, which is known as the QUADRA study, was basically a single-arm phase 2 study of the PARP inhibitor niraparib, and it was in all-comers. Anyone for whom the provider felt like a PARP inhibitor was a reasonable option, and they had received at least 3 lines of chemotherapy and had high-grade serous or high-grade endometrial ovarian cancer, could come on QUADRA. The endpoint was response rate.

The primary group we were looking at in QUADRA was this group of patients who were in the fourth line or beyond—really particularly the fourth and fifth lines of therapy—who still were considered appropriate for platinum or were platinum-sensitive, although that’s kind of hard to define. But they were appropriate for platinum, and had evidence on their tumor that they had lost their homologous recombination proficiency. They were homologous recombination deficient [HRD].

So the primary group of interest in QUADRA was appropriate for platinum, homologous recombination deficient, advanced ovarian cancer.

That group of patients performed very well, with a response rate of about 27%, and it was a very durable response. Again, remember that we’re in the fourth and the fifth line and patients were on a median of almost 10 months—9.5 months. Even more encouraging was the fact that their median overall survival was almost 20 months. And so, we’re in fourth- and fifth-line settings and we still have patients, on average, who are almost going another 2 years or more following QUADRA.

This is a very encouraging signal. When we pulled out the patients who hadBRCAmutations, the majority of whom were PARP-naïve, who just had missed the indications up to that point, the response rates were even higher—at 39%—with similar durations of response and a similar looking median overall survival. So even in late lines of therapy, certainly we know that PARP inhibitors perform best the earlier you use them.

But I think the message from QUADRA: We still have, as I said, the incredible prevalence of women living with recurrent ovarian cancer or who, unfortunately, will still recur in the future and aren’t going to have the opportunity to get a frontline PARP because that time has passed. They are still going to present in later lines of therapy, and QUADRA gives us a lot confidence that a PARP inhibitor can actually be a very effective therapy to consider instead of chemotherapy. Certainly, a 27% response rate and median duration of 9 months. Again, it’s a single-arm phase 2 study, but just looking at historical controls of 10% to 15% and 3 to 4 months sounds like, potentially, a better option for patients.

And so, this particular indication, and it is public knowledge, has been submitted to the FDA, and hopefully will allow for expansion of the label so that patients beyondBRCAcan access a PARP inhibitor as monotherapy. This would be the first indication for monotherapy treatment—not as maintenance, but instead of chemotherapy, monotherapy PARP inhibitor treatment for their cancer outside of patients with a somatic or germlineBRCAmutation. This will tremendously expand the opportunities for our patients to access PARP inhibitors in a setting of their choice.

Some patients may not want to be reinduced with platinum again. Or they may have a platinum allergy. And so, trying to get to that maintenance PARP option just isn’t possible for them. If this were approved, you actually could, with some biomarker selection, the HRD, go right to a PARP inhibitor for appropriate patients. That is an exciting possibility. We’ll know later in the fall of 2019 whether that actually happens, but I think that’s really where the field is going. And then, even beyond that is combination therapy. So again, at ASCO [the American Society of Clinical Oncology annual meeting] 2019, we saw a presentation of a randomized phase 2 trial that uses niraparib and bevacizumab.

Again, we’ve been talking a lot about either/or—bevacizumab or PARP. Here they’ve combined them versus niraparib alone. In both patients withBRCA-associated cancers and non, the combination markedly improved response rate and progression-free survival. This was a small randomized phase 2 trial, but now there is the randomized phase 3 study that will be versus chemotherapy in a platinum-sensitive population. Again, replacing chemotherapy potentially with targeted therapy here—a PARP plus bevacizumab. And again, potentially expanding beyond theBRCAbiomarker. So that’s incredibly exciting and it’s happening now as well. That may open up non-chemotherapeutic options for our patients with platinum-sensitive disease, which is an exciting potential. It adds another line of active therapy for our patients. It keeps them alive longer with a good quality of life. That’s what we’re here to do until we can cure 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