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.
OncLive: Please provide some background information on this study.
: 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.
What was the design of the study?
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.