Abstract CT157: An open-label Phase II study of combination of TSR-042, bevacizumab, and niraparib in patients with platinum-resistant ovarian cancer (OC): Cohort A of the OPAL trial
Authors: Liu Joyce , Gunderson Camille , Hendrickson Andrea Wahner , Ratner Elena , Diver Elisabeth , Moroney John , Arend Rebecca C. , Louie-Gao Melinda , Wang Sarah , Luptakova Katarina , Konecny Gottfried E. 
Published: August 2019

Background: Most patients with advanced OC relapse after initial standard platinum-based chemotherapy, and eventually the disease becomes platinum-resistant. Niraparib (ZEJULA®) was the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the United States and Europe for maintenance treatment in patients with recurrent OC regardless of BRCA mutation status. Preclinical evidence suggests that niraparib activates the stimulator of interferon genes pathway to increase immune cell infiltration and synergizes with anti-PD-1 therapy. Additionally, hypoxia induces contextual synthetic lethality by impairing homologous recombination, and therefore induction of hypoxia by inhibition of angiogenesis could lead to synergy with PARPi. In the TOPACIO/KEYNOTE-162 trial, niraparib in combination with pembrolizumab has shown efficacy in recurrent, platinum-resistant OC. Niraparib in combination with the anti-angiogenic agent bevacizumab is under study for the treatment of recurrent platinum-sensitive OC (AVANOVA trial) and advanced OC following response on frontline platinum-based chemotherapy (OVARIO trial). TSR-042 is an anti-PD-1 humanized monoclonal antibody that has shown clinical activity as monotherapy in early phase trials. Cohort A of the OPAL trial will evaluate the novel triple combination of the PARPi niraparib, angiogenesis inhibitor bevacizumab, and PD-1 inhibitor TSR-042 in patients with platinum-resistant OC who are naïve to PARPi therapy.

Methods: Eligible patients will have high-grade recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer of the ovary and progressed ≤6 months from completion of ≥4 cycles of platinum-based chemotherapy. Additional key eligibility criteria include 1-2 prior lines of anticancer therapy for OC, no prior therapy with an anti-PD-1 or anti-PD-L1 antibody, and no prior therapy for OC with a PARPi. Patients will receive a combination regimen of 500 mg TSR-042 on day 1 of each 3-week cycle for 4 cycles, then 1000 mg on day 1 of every other cycle beginning on cycle 5 until progression or toxicity, 15 mg/kg bevacizumab on day 1 of each 3-week cycle for up to 15 months, and niraparib 300 mg or 200 mg (for patients &lt;77 kg or platelet count &lt;150,000/µL at screening) daily until disease progression or toxicity. The primary endpoint is to evaluate treatment efficacy by confirmed objective response rate per investigator-assessed RECIST v1.1 criteria. Secondary objectives are evaluation of progression-free survival, overall survival, duration of response, and disease control rate. Exploratory objectives are to identify potential biomarkers of tumor response, including BRCA status and homologous recombination repair gene status and to evaluate the evolution of the molecular profile of the tumor and tumor microenvironment in response to treatment.

Clinical trial identification: NCT03574779

Citation Format: Joyce Liu, Camille Gunderson, Andrea Wahner Hendrickson, Elena Ratner, Elisabeth Diver, John Moroney, Rebecca C. Arend, Melinda Louie-Gao, Sarah Wang, Katarina Luptakova, Gottfried E. Konecny. An open-label Phase II study of combination of TSR-042, bevacizumab, and niraparib in patients with platinum-resistant ovarian cancer (OC): Cohort A of the OPAL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT157.