A global phase 3 study (ENGOT-OV44/FIRST) with an adaptive design is examining the efficacy of an investigational anti–PD-1 humanized monoclonal antibody (dostarlimab) plus chemotherapy followed by niraparib (Zejula) and dostarlimab maintenance therapy with standard platinum-based chemotherapy in women with stage III or IV high-grade nonmucinous epithelial ovarian cancer. Dostarlimab has shown clinical activity as monotherapy in this patient population in early phase trials.
The study design was described by Anne-Claire Hardy-Bessard, MD, Medical Oncologist, CARIO-NPCA, Plevin, and Cooperative Gynecological Cancer Research Group (GINECO), Paris, France, during the 2020 virtual scientific program of the American Society of Clinical Oncology.
The study is currently enrolling patients, with a planned enrollment of 1228 patients. The original design had 3 arms.
- Arm 1 was to receive standard of care (carboplatin plus paclitaxel plus bevacizumab) in cycle 1 followed by standard of care plus dostarlimab placebo from cycles 2 to 6, and maintenance treatment using bevacizumab (with niraparib placebo and dostarlimab placebo).
- Arm 2 is an active comparator arm in which patients receive standard of care in cycle 1 followed by standard-of-care chemotherapy, dostarlimab placebo from cycles 2 to 6, and maintenance treatment of bevacizumab with niraparib and dostarlimab placebo.
- Arm 3 is an experimental arm in which participants receive standard of care plus dostarlimab. Participants in this arm will receive standard of care in cycle 1 followed by standard-of-care chemotherapy, dostarlimab, and maintenance treatment of bevacizumab with niraparib and dostarlimab.
The study has an adaptive design for modification of the control arm updated to reflect the standard of care. “In 2018, after positive results from the SOLO-1 trial, all patients with BRCA-mutated disease were randomized to arm 2 or arm 3 to ensure that they receive niraparib maintenance and not placebo,” said Dr Hardy-Bessard. “In 2019, after the PRIMA trial demonstrating the efficacy of niraparib in all patients, regardless of biomarker, amendment 4 closed arm 1 to ensure that all patients are receiving niraparib.”
The multicenter, randomized, double-blind, controlled study has 2 primary outcome measures:
- To compare the rate of progression-free survival (PFS) in patients whose tumors express PD-L1 who are treated with platinum-based combination therapy, dostarlimab, and niraparib to standard-of-care platinum-based combination therapy as first-line treatment.
- To compare the PFS of all participants treated with platinum-based combination therapy, dostarlimab, and niraparib to standard-of-care platinum-based combination therapy.
Patients will be stratified according to concurrent bevacizumab use, homologous recombination repair mutation status, and disease burden.
Eligible patients are those with a histologically confirmed diagnosis of high-grade nonmucinous epithelial ovarian (eg, serous, endometrioid, clear-cell, carcinosarcoma, and mixed pathologies), fallopian tube, or primary peritoneal cancer that is stage III or IV according to the International Federation of Gynecology and Obstetrics system or tumor, node, and metastasis staging criteria.
All participants with stage IV disease are eligible. Participants with stage III are eligible if they have had Completeness of Cytoreduction score 0 resection with ≥5 cm extra-pelvic disease following primary debulking surgery, have inoperable stage III disease, have macroscopic residual tumor following primary debulking surgery, or if neoadjuvant chemotherapy is planned.