Matulonis Highlights Niraparib, Immunotherapy Data in Ovarian Cancer

Ursula A. Matulonis, MD

Niraparib (Zejula) demonstrated durable antitumor activity in patients with heavily pretreated homologous recombinant deficiency (HRD)-positive ovarian cancer, according to data from the phase II QUADRA trial.

The PARP inhibitor is currently FDA approved as a maintenance therapy for patients with ovarian cancer, regardless of BRCA status. The single-arm QUADRA study, results of which were presented at the 2018 ASCO Annual Meeting, is aimed to test the oral agent’s activity in patients with HRD-positive recurrent disease. The primary endpoint was overall response rate (ORR).¹

In patients with HRD-positive, platinum-sensitive disease who received ≥3 prior lines of treatment without a PARP inhibitor, the ORR was 27% (14/51). Duration of response (DOR) for this cohort was 9.2 months. The ORR was 29% among patients receiving treatment in the fourth- and fifth-line settings. Toxicity levels were consistent with other niraparib studies and became manageable with dose reductions.

KEYNOTE-100 was another notable study in this setting presented at the 2018 ASCO Annual Meeting. The large, phase II trial indicated that single-agent pembrolizumab (Keytruda) demonstrated significant antitumor activity in patients with PD-L1—positive advanced ovarian cancer. Patients were divided into 2 cohorts based on level of prior treatment and combined positive score (CPS), said lead study author Ursula A. Matulonis, MD.

Data presented suggested that ORR increased with PD-L1 expression. Total ORR for the 376 patients was 8.0%. Across both cohorts, for patients with a CPS ≥1, ORR was 10.2%; for CPS ≥10, it was 17.1%.²

OncLive: Please provide some background to the QUADRA study.

What was the study design?

What were the data presented at the 2018 ASCO Annual Meeting?

Are there any additional data you would like to mention?

In an interview with OncLive, Matulonis, chief of the Gynecological Oncology Division at Dana-Farber Cancer Institute and professor of Medicine at Harvard Medical School, highlighted the activity and tolerability of niraparib and discussed other recent data in ovarian cancer.Matulonis: The rationale for QUADRA was really to expand the use of the oral PARP inhibitor niraparib into patient populations beyond where it's currently FDA approved. Currently, it is FDA approved for maintenance therapy in women who have responded to platinum-based chemotherapy and have recurrent disease. In order to prolong that maintenance and that remission they have achieved, the FDA granted approval to niraparib as a very broad label. Using niraparib following chemotherapy at a dose of 300 mg—so once somebody's blood counts have come back up to normal—they're ready to go on a PARP inhibitor.This is a very large trial looking at single-agent niraparib in more heavily pretreated populations. The total number of participants enrolled was 463, and after a little more than 300 women had been enrolled, an amendment was then issued stating that patients were limited to 3 or 4 prior lines of therapy and they had to have an initial response to chemotherapy. This was to ensure that their disease had some susceptibility to drugs such as PARP inhibitors.The full data issued really looked at the primary endpoint, which was ORR in heavily pretreated patients with HRD-positive ovarian cancer. There was a 29% ORR, and this is exciting because these are patients with few options once they get to the fourth-line setting and beyond. Overall, this is a good thing.Other results being presented are around the germline BRCA-mutated cohort. This is a subgroup of patients with underlying BRCA mutations. In that population of heavily pretreated women with 3 or 4 prior lines of therapy, there are excellent response rates. In these women with platinum-sensitive disease, there was a little greater than 40% ORR, which is very impressive. For patients with platinum-resistant cancer, it was still very good at around 25% ORR. Overall for the BRCA-mutated group, the ORR was close to 30%.

The other telling part of these results is the DOR. For BRCA-positive patients, it was more than 9 months. For HRD-positive patients, DOR was a little longer than 8 months. In terms of safety, no new safety signals were observed. We did see a necessity for dose reductions from 300 mg to 200 mg, and even sometimes down to 100 mg.

What the next steps with these data?

What is the key message from this study that you would like oncologists to take home?

Moving on to KEYNOTE-100, can you please share some background to this trial?

However, that's not dissimilar from other trials. The ENGOT-OV16/NOVA data presented at the Society of Gynecologic Oncology Annual Meeting on Women's Cancer showed that women with baseline platelet counts of less than 150,000 should be started at 200 mg to avoid hematologic toxicities. It's interesting that in the NOVA study, dropping dose did not seem to affect efficacy. Therefore, we are confident that 200 mg is the right dose.Because of the large patient population, we need to analyze the different subsets even more than what has already been done. We need to see where else niraparib can be used. For example, we had HRD-positive patients, BRCA-positive patients, and even patients who had been previously treated with a PARP inhibitor.For women with high-grade ovarian cancer, PARP inhibitors are an amazing agent to use. We should be thinking about how we can use these drugs in our patients, either through maintenance therapies or now as treatment options.This is the largest trial of single-agent immunotherapy to treat patients with recurrent ovarian cancer. The drug here is pembrolizumab. It was used at 200 mg intravenously every 3 weeks and maintained for 2 years, or until prohibitive toxicities or death. We had 376 patients enrolled in this trial, and we divided them into 2 cohorts. Cohort A comprised patients who had 1 to 3 prior lines of treatment and a platinum-free interval between 3 and 12 months. Cohort B was patients who received 4 to 6 prior lines of treatment and they had to have a platinum-free interval of ≥3 months. Two-thirds of patients were in cohort A.

Please provide the analysis of the GOG-258 trial that was also presented.

The purpose of this trial was to look at 2 things: ORR by cohort, and secondly, by CPS. Basically, the CPS score is the number of cells that are PD-L1 positive, divided by tumor cells, multiplied by 100. When we looked at cohorts A and B in terms of ORR, we saw 7.4% in cohort A and 10% in cohort B. It's interesting that when you look at these responses—and there were 30 responses out of 376 patients—it was important to see responses in all types of histology. We also saw them regardless of the level of pretreatment. This suggests that immuno-oncology agents can work in more heavily pretreated patient populations. Then, we looked at CPS. We saw that as you went higher in the CPS score, the ORR also went up. We saw the same thing in the extra patients from cohort A and in cohort B. Low CPS score had an ORR of 3.7%, CPS 1 to 10 was around 10%, and CPS >10 was actually 17%. The only issue here is that as CPS score goes higher, very few of those patients have a high PD-L1 expression. However, it is a solid subset of patients who may benefit from immunotherapy.I presented a poster on GOG-258, specifically the patient-reported outcomes (PROs). This was a study presented at the 2017 ASCO Annual Meeting, which looked at patients with stage III/stage IV endometrial cancer. The 2 arms were 6 cycles of carboplatin/paclitaxel or a combination of radiotherapy to the pelvis and a shortened duration of chemotherapy.

What we saw last year was not a significant difference in terms of progression-free survival for these groups. What I presented at the 2018 ASCO Annual Meeting were the PROs. In both groups, patients did experience significant neuropathy because of the chemotherapy. These effects were long lasting for patients. Secondly, in the radiation group, patients had a high level of gastrointestinal toxicity. These are important issues to remember when selecting therapies.

References

1. Moore K, Alvarez Secord A, Geller M, et all. QUADRA: a phase 2, open-label, single-arm study to evaluate niraparib in patients (pts) with relapsed ovarian cancer (ROC) who have received ≥3 prior chemotherapy regimens. J Clin Oncol. 2018;36(suppl; abstr 5514).
2. Matulonis U, Shapira R, Santin A, et all. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: interim results from the phase 2 KEYNOTE-100 study. J Clin Oncol. 2018;36(suppl; abstr 5511).