Expert Highlights Promising Results With Pembrolizumab/Niraparib in Platinum-Sensitive Ovarian Cancer

Panagiotis A. Konstantinopoulos, MD

Panagiotis A. Konstantinopoulos, MD

The phase I/II TOPACIO trial showed promising results for patients with platinum-resistant/refractory ovarian cancer. The combination regimen of the PARP inhibitor niraparib (Zejula) plus the PD-1 inhibitor pembrolizumab (Keytruda) achieved disease control in 68% of the patient population.

PARP inhibitors have previously been approved as monotherapy for the treatment of ovarian cancer, but the responses in patients with platinum-sensitive disease have been very low and limited. While PD-1 inhibitors have had decent responses in this patient population, investigators sought to discover if there was a benefit to combining a PARP inhibitor with a PD-1 inhibitor for these difficult-to-treat patients.

In results reported at the 2018 ASCO Annual Meeting, patients with BRCA wild-type or homologous recombination deficiency (HRD)-negative disease had a significantly improved overall response rate compared to PARP inhibitor monotherapy, ranging from 24 to 27%.

“We can see those responses in patient populations like BRCA wild-type, platinum-resistant, or BRCA platinum-refractory patients, regardless of their BRCA mutation status, where the response to a PARP inhibitor as a single agent would be very small,” said lead study author Panagiotis A. Konstantinopoulos, MD. “In a way, we are able now to expand the use of PARP inhibitors in difficult-to-treat populations where PARP inhibitor monotherapy has very, very limited efficacy.”

Moving forward, the combination will be investigated further in a larger trial. According Konstantinopoulos, niraparib will be studied in combination with TSR-042, another PD-1 inhibitor.

In an interview withTargeted Oncology, Konstantinopoulos, director of Translational Research, Gynecologic Oncology Program at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School, discussed the findings from the TOPACIO trial for patients with platinum-sensitive ovarian cancer. He also highlights the outlook for immunotherapy in gynecologic cancers and what the next steps are moving forward.

TARGETED ONCOLOGY:Can you begin by discussing the rationale and some of the background for the TOPACIO study?

Konstantinopoulos:Platinum-resistant and platinum-refractory ovarian cancer is a disease of an important unmet need as there are very limited treatment options for these patients. Bevacizumab in combination with chemotherapy is currently FDA approved based on the AURELIA study, which was done on patients who had up to 2 prior lines of chemotherapy.

In patients with platinum-resistant disease, PARP inhibitors have shown very limited activity as monotherapy. In patients withBRCA-mutated platinum-resistant disease, the objective response rate (ORR) is 25% to 30%, which has led to the FDA approval. However, outside that setting, in the BRCA wild-type platinum-resistant disease, the ORR is only 5%. InBRCA-mutated platinum-refractory patients, the ORR is only 0% to 14%. Furthermore, if you look at PD-1 and PD-L1 inhibitor therapy in ovarian cancer, the ORR has been modest, essentially around 10%, which is expected of PD-L1 status. It's about 9.7% for avelumab (Bavencio) and 11% for pembrolizumab.

The question of the TOPACIO study was whether combining those 2 agents would get better efficacy in difficult-to-treat populations in ovarian cancer, specifically platinum-resistant and platinum-refractory disease. This was based on a number of preclinical data suggesting that there was synergism between the 2 agents, which was irrespective of BRCA mutation status and irrespective of PD-L1 status.

To summarize those preclinical data very briefly, PARP inhibitors can induce double-strand breaks, which can lead to activation of the immune system either through increased neoantigens or through activation of the STING pathway, which is a very important pathway involved in the innate immunity. PARP inhibitors can also upregulate PD-L1 expression. That can happen through activation of the double-strand break, ATM/ATR Chk1 checkpoint, and that can lead to PD-L1 upregulation. The combination of immune activation together with PD-L1 overexpression provides the necessary immune priming for the tumor cancer cells to respond to the immunotherapy.

TARGETED ONCOLOGY:How was this trial designed?

Konstantinopoulos:The TOPACIO study was a phase I/II study. In the phase I study, the recommended phase II dose was determined. There were 2 dose levels assessed. The first dose level was 300 mg of niraparib once daily and pembrolizumab 200 mg intravenously (IV) every 3 weeks. Two out of 6 patients developed thrombocytopenia at that dose, so we went down to 200 mg of niraparib once daily and 200 mg of IV pembrolizumab every 3 weeks. That was actually the recommended phase II dose that moved to the phase II portion of the study where the primary objective was objective response rate by investigator assessment by RECIST 1.1.

The key eligibility criteria for this study was that patients needed to be initially platinum-sensitive, so they needed to have progressed at least 6 months from completion of their first-line platinum-based chemotherapy. They also needed to be platinum-resistant as per an investigator assessment. Primary platinum-refractory patients were not allowed, but patients who had subsequent platinum-refractory disease — meaning they progressed during or within 1 month of the last platinum therapy – could participate on the study. Up to 5 prior lines of therapy were also allowed. It's important to underscore that patients who were platinum-sensitive but could not receive further platinum for any reason – meaning, platinum-ineligible patients – were included in the study.

TARGETED ONCOLOGY:Can you share some of the baseline characteristics?

Konstantinopoulos:The important thing is that 63% of these patients had previously received bevacizumab. This is very important, because these patients were not essentially eligible for a bevacizumab-containing regimen as introduced in the AURELIA study. Furthermore, there was appropriate representation of the chemotherapy agents used in ovarian cancer. Of the patients on the study, 29% had an ECOG performance status of 1. The median prior lines of therapy was 2.

In terms of platinum-sensitivity resistance and platinum-refractory status, I want to say that 79% of these patients were platinum-resistant or platinum-refractory, while 21% were platinum-ineligible, as in platinum-sensitive but could not get more platinum.

TARGETED ONCOLOGY:What were the findings discovered in this trial?

Konstantinopoulos:As of the April 2, 2018 data cutoff, the ORR was 25%. Essentially, there were 15 responses out of 60 evaluable patients. Eleven of the 15 responses were confirmed. There were also 3 patients with complete response and 12 patients with a partial response. Nine patients continued on the study, 7 with objective response and 2 with stable disease.

I think the most important finding of the study is that we saw responses across all different patient subgroups. We saw responses in patients who were PD-L1-positive or PD-L1-negative. We saw responses in patients who were platinum-sensitive, platinum-resistant, or platinum-refractory. We saw responses in patients who wereBRCAmutated or not, HRD-positive or HRD-negative, and among patients who had previously received bevacizumab or who did not. There was activity that was consistent across different subtypes of patients.

Most importantly, I think what stands out is the ORR that we saw in patients with the tumor BRCA (tBRCA) wild-type and HRD-negative populations. There, the response rate was 24% in the tBRCAwild-type and 27% in the HRD-negative population who were platinum-resistant.

To put this into perspective, we have to think that this is a very resistant population to chemotherapy, where for PARP inhibitors themselves, the efficacy is only 5%. With the addition of the immunotherapy, we were able to obtain objective response rates in the range of 24 to 27%, which is essentially the FDA approved PARP inhibitor efficacy that we've seen with the FDA approval of PARP inhibitors inBRCA-mutated platinum-resistant ovarian cancer. We're very excited about the efficacy of this combination in the tBRCAwild-type and HRD-negative population.

Furthermore, among patients who were platinum-refractory — meaning they progressed during or within 1 month after their last platinum therapy – we saw an ORR that was 23% in the tBRCAwild-type and 25% in the HRD-negative population. This is a very important finding, again, because this is a very resistant population. With PARP inhibitor monotherapies, there is a 0% response for tBRCAwild-type and only 0% to 14% in patients withBRCA-mutated disease.

Overall, I think we were able to show with this study that the combination of a PARP inhibitor and a PD-1 inhibitor can achieve responses that we've seen with PARP inhibitor monotherapy inBRCA-mutated patients. Thereby, we can see those responses in patient populations likeBRCAwild-type, platinum-resistant, or BRCA platinum-refractory patients regardless of their BRCA mutation status where the response to a PARP inhibitor as a single agent would be very small. In a way, we are able now to expand the use of PARP inhibitors in difficult-to-treat populations where PARP inhibitor monotherapy has very, very limited efficacy.

TARGETED ONCOLOGY:What do you envision the future of immunotherapy will be in gynecologic cancers?

Konstantinopoulos:Although immunotherapy has had some excellent responses in a number of tumor types, unfortunately, the responses that we have seen in ovarian cancer have been modest. The most important priority for gynecologic cancers and ovarian cancer research is to improve the response rate of immunotherapy in this disease.

There are a number of approaches that have been tried, for example, the addition of antiangiogenic therapy to immunotherapy, and the addition of chemotherapy or targeted therapy, like PARP inhibitors. We are very excited about the approach of the addition of the PARP inhibitor to immunotherapy, because there is good preclinical rationale. I think we've seen a number of patient populations where PARP inhibitors by themselves had very limited activity and that the combination was very, very successful and significantly better than PARP inhibitor monotherapy.

TARGETED ONCOLOGY:What are your next steps for this study?

Konstantinopoulos:The next step for the study is to move to a larger single-arm study of this combination with the possibility of a registration pathway through the FDA. As a reminder, PARP inhibitors were initially approved by the FDA based on the ORR and the duration of response.

The duration of response that we saw in this study was 9.3 months, which compares very well to the duration of response that we've seen with PARP inhibitors inBRCA-mutated platinum-resistant disease within their FDA approved indication. Based on what we have so far, we will be moving along in a bigger single-arm study of the combination of niraparib with a PD-1 inhibitor called TSR-042, with a goal of particularly focusing on populations like BRCA wild-type, platinum-resistant, and platinum-refractory, regardless ofBRCAmutation status. There will be a goal of achieving objective response rates and duration of response like we saw in this study, which are very comparable if not better than the FDA approved objective response rate and duration of response of PARP inhibitor monotherapy inBRCA