Panagiotis A. Konstantinopoulos, MD, PhD, discusses the findings of the TOPACIO/KEYNOTE-162 study and the future for PARP inhibitor combinations and immunotherapy overall in ovarian cancer.
Panagiotis A. Konstantinopoulos, MD, PhD
PARP inhibitors have made a splash in the ovarian cancer landscape, particularly for those with BRCA-mutated tumors. The benefit of these agents as monotherapy has been limited in the platinum-resistant/refractory settings, but there may be hope in combination with immunotherapy, according to Panagiotis A. Konstantinopoulos, MD, PhD.
The phase I/II TOPACIO/KEYNOTE-162 study (NCT02657889) evaluated the combination of niraparib (Zejula) plus pembrolizumab (Keytruda) in patients with recurrent ovarian cancer. Findings from the study presented at the 2018 ASCO Annual Meeting showed that among 60 evaluable patients, the overall response rate (ORR) was 25%. Overall, the duration of response (DoR) was 9.3 months. Additionally, in the 12 patients with BRCA-mutated tumors, the ORR was 42%.
Niraparib is currently FDA approved for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
In an interview with OncLive®, Konstantinopoulos, director of Translational Research, Gynecologic Oncology, Dana-Farber Cancer Institute, associate professor of Medicine, Harvard Medical School, and lead TOPACIO/KEYNOTE-162 investigator, discussed the findings of the study and the future for PARP inhibitor combinations and immunotherapy overall in ovarian cancer.Konstantinopoulos: Platinum-resistant/refractory ovarian cancer is an important unmet need, as there are very limited treatment options for these patients. Bevacizumab (Avastin) in combination with chemotherapy is currently FDA approved based on the AURELIA study, which was done in patients with up to 2 prior lines of chemotherapy. In patients with platinum-resistant disease, PARP inhibitors have shown very limited activity as monotherapy. In patients with BRCA-mutated platinum-resistant disease, the ORR is 25% to 30%, which has led to their FDA approval. However, outside that setting, in BRCA wild-type, platinum-resistant disease, the ORR is only 5%. In BRCA-mutated platinum-refractory disease, the ORR is 0% to 14%.
Furthermore, if we look at PD-1/PD-L1 inhibitor therapy in ovarian cancer, the ORR has been modest. Essentially, it is around 10%, irrespective of PD-L1 status, and it is about 9.5% for avelumab (Bavencio) and 11% for pembrolizumab. The question of the TOPACIO study was whether combining [pembrolizumab and niraparib] will give us better efficacy in difficult-to-treat populations of ovarian cancer, specifically platinum-resistant and platinum-refractory disease. This was based on preclinical data, which suggested synergy between the 2 agents, irrespective of BRCA mutation status [and] PD-L1 expression.
To briefly summarize the preclinical data, PARP inhibitors can induce double-strand breaks, which can lead to activation of the immune system either through increased neoantigens and activation of the STING pathway, which is a very important pathway involved in innate immunity. PARP inhibitors can also upregulate PD-L1 through the activation of a double-strand break in ATM- and ATR-Chk1, and that can lead to PD-L1 upregulation. The combination of immune activation together with the PD-L1 overexpression provides necessary immune priming for the cancer cells to respond to immunotherapy.TOPACIO was a phase I/II study. In phase I, the recommended phase II dose was determined and 2 dose levels were assessed. The first dose level was 300 mg of niraparib once daily and 200 mg of pembrolizumab intravenously (IV) every 3 weeks. Two of the 6 patients developed thrombocytopenia in that dose, so we went down to 200 mg of niraparib once daily and 200 mg of IV pembrolizumab every 3 weeks. That was the recommended dose that moved to the phase II portion of the study, where the primary objective was investigator-assessed ORR by RECIST v1.1 criteria.
The key eligibility criteria for this study was platinum sensitivity, so patients must have progressed 6 months from completion of their first-line platinum-based chemotherapy. But, they needed to be platinum-resistant. Primary platinum-refractory patients were not allowed, but patients who had subsequent platinum-refractory disease—who progressed during or within 1 month of their last platinum therapy—could participate. Up to 5 prior lines of therapy were allowed. It is important to underscore that patients who were platinum-sensitive but could not receive further platinum for any reason, were included in the study.
The important thing is that 63% of these patients had previously received bevacizumab, so these patients were not eligible for a bevacizumab-containing regimen as introduced in the AURELIA study. Furthermore, all patients had previously received chemotherapy. Of these, 29% had an ECOG performance status of 1. The median prior lines of therapy was 2, and 79% of these patients were platinum-resistant or platinum-refractory, while 21% were platinum-ineligible.As of the April 2, 2018, data cutoff, the ORR was 25%. Essentially, there were 15 responses out of 60 evaluable patients. Eleven of those 15 responses were confirmed. Three patients achieved a complete response and 12 patients had a partial response. Nine patients continue on the study, 7 with objective response and 2 with stable disease.
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, and platinum-refractory. We saw responses in patients who were BRCA-mutated and not, homologous recombination deficient positive or negative, or had previously received bevacizumab or not. Activity was consistent across different subtypes of patients.
What stands out is the ORR that we saw in patients with BRCA wild-type and HRD-negative tumors. There, the response rate was 24% in the BRCA wild-type population, and 27% in the HRD-negative population. To put this into perspective, we have to think about how this is a population that is very resistant to chemotherapy, where PARP inhibitors alone have low efficacy. With the addition of immunotherapy, we were able to obtain an ORR in the range of 24% to 27%, which is essentially the FDA-approved PARP inhibitor efficacy that we have seen in BRCA-mutated platinum-resistant ovarian cancer.
We are very excited about the efficacy of this combination in the BRCA wild-type and HRD-negative patient population. Furthermore, among patients who were platinum-refractory, we saw an ORR of 23% in the BRCA wild-type and 25% in the HRD-negative population, which is a very important finding because this is a very resistant patient population with PARP inhibitor monotherapy.
The DoR that we saw in the study was 9.3 months, which compares very well with the DoR with PARP inhibitors in BRCA-mutated platinum-resistant disease within their FDA-approved indication.
Overall, we showed that the combination of a PARP inhibitor and a PD-1 inhibitor can achieve responses that we have seen with PARP inhibitor monotherapy in BRCA-mutated patients. In a way, we are now able to expand the use of PARP inhibitors in difficult-to-treat populations where PARP inhibitor therapy has limited efficacy.Although immunotherapy has shown excellent responses in a number of tumor types, the responses that we have seen in ovarian cancer have unfortunately been modest. The priority right now for gynecologic 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, such as the addition of antiangiogenic therapy, chemotherapy, and targeted therapies to immunotherapy. We are very excited about the addition of PARP inhibitors to immunotherapy, and there is a good preclinical rationale.
The next step following these findings is to move to a larger single-arm study of this combination, with the possibility of a registration trial through the FDA. As a reminder, PARP inhibitors were originally approved by the FDA based on ORR and DoR.
Based on what we have so far, we will move on to a large, single-arm study of niraparib with a PD-1 inhibitor called TSR-042, specifically focusing on populations like BRCA wild-type, platinum-resistant, and platinum-refractory tumors, regardless of BRCA mutation status. The goal is to achieve an ORR and DoR that are comparable, if not better, than the ORR and DoR of PARP inhibitor therapy in BRCA-mutated platinum-resistant disease.
Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/KEYNOTE-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. J Clin Oncol. 2018;36(suppl; abstr 106).