A combination of Zejula (niraparib) and Keytruda (pembrolizumab) is well-tolerated and has promising anti-tumor activity in women with ovarian carcinoma who have failed prior platinum-based chemotherapy, results from a Phase 1/2 trial show.
Overall, 18% of the patients responded to the combo regimen, regardless of platinum resistance, BRCA mutations, or prior treatment with bevacizumab (brand names Avastin, Mvasi, and Zirabev), warranting further investigation in a larger trial, the researchers said.
Response rates seemed particularly significant for patients without BRCA or other DNA repair mutations.
The data were described in the report, “Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma,” published in the journal JAMA Oncology.
Zejula is approved as a maintenance therapy for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who have had a complete or partial response to platinum-based therapy. The medicine is taken as a once-daily pill and can be used in women with or without germline, or inherited, mutations in BRCA genes.
It is a poly (ADP-ribose) polymerase (PARP) inhibitor, which means it works by blocking the activity of PARP proteins — enzymes involved in the repair of damaged DNA inside cells. Zejula is marketed by Tesaro, a GSK company.
Keytruda is an anti-PD-1 antibody given as into-the-vein injections. It is approved for several solid and some blood cancers. It belongs to the class of immune checkpoint inhibitors, and works by boosting the immune response against tumor cells. Keytruda is sold by Merck (known as MSD outside the United States and Canada).
Preclinical studies have suggested that these two approaches combined have a greater effect in ovarian cancers, regardless of BRCA mutations. The TOPACIO Phase 1/2 trial (NCT02657889) was conducted to confirm the findings and determine the safety of this combination.
TOPACIO included women with ovarian cancer — including epithelial ovarian, fallopian tube, or primary peritoneal cancer — whose disease returned (resistant) or failed to respond (refractory) to platinum-based therapy. It also evaluated the treatment for patients with advanced or metastatic triple-negative breast cancer.
The trial was an open-label, single-group study with two phases: a Phase 1 dose escalation study to determine dose-limiting toxic effects and establish the recommended Phase 2 dose (RP2D); a subsequent Phase 2 to evaluate the combo’s efficacy, given at the doses established in Phase 1.
There were 62 women enrolled at multiple sites in the U.S. Median follow-up was 12.4 months.
Among the 60 patients available for efficacy analysis, the combination shrank tumors in 12 (18%), including three (5%) who experienced a complete response (disappearance of tumors).
An additional 28 patients (47%) experienced disease stabilization after treatment, leading to a disease control rate of 65%.
Responses were similar across patient groups, irrespective of their sensitivity to platinum-based therapy (if they were resistant, refractory or had undetermined sensitivity), whether they had been treated with prior bevacizumab, or whether their tumors had BRCA or other DNA repair mutations (causing homologous recombination deficiency, HRD).
Compared with monotherapy with Zejula or Keytruda, the combo appears to improve efficacy in patients negative for BRCA or HRD mutations — 19% of these patients reached a response.
Ovarian cancer patients who lack a BRCA mutation and are resistant or refractory to platinum-based therapy have poor responses to single-agent PARP inhibitors such as Zejula — ranging between 0% to 5%. Similarly, single-agent PD-1/PD-L1 inhibitors, such as Keytruda, have a response rate of 4% to 10% in platinum-resistant ovarian carcinoma irrespective of PD-L1 levels.
In this trial, the median duration of response was not reached, ranging from 4.2 to 14.5 months. At the time of data cutoff — over two years of study — three patients continued to receive treatment, two with a response and one with stable disease.
Through the course of the trial, 59 patients discontinued treatment because of: radiologically detected disease progression (41 patients), clinical disease progression (eight), an adverse event (five), patient request (four), and a move out of the country (one).
“This study has shown that the combination treatment of niraparib [Zejula] and an anti-PD-1 antibody [Keytruda] appears to be well-tolerated and potentially provides clinical activity by tumor shrinkage and disease stabilization in patients with recurrent ovarian carcinoma,” the researchers said.
The observed response rates are “of interest,” especially for patients without BRCA or HRD-related mutations, who typically respond poorly to these types of therapies, the researchers stressed.
“No new toxicity signals were observed, and the regimen could represent a potential new therapeutic option in this patient population,” they said. However, they noted that a larger trial is needed to validate these results.