A pembrolizumab/olaparib strategy significantly improved progression-free survival in patients with newly diagnosed BRCA-nonmutated advanced epithelial ovarian cancer, although overall survival was not improved. Ignace Vergote, MD, PhD, and colleagues reported results from the phase III ENGOT-OV43/GOG-3036/KEYLYNK-001 trial, which evaluated pembrolizumab plus chemotherapy followed by pembrolizumab/olaparib maintenance, in The Lancet Oncology.
The three-arm design helped clarify the source of the progression-free survival benefit: pembrolizumab without olaparib did not improve progression-free survival compared with the control regimen.
Study Details
The double-blind trial enrolled 1,367 patients with previously untreated stage III or IV epithelial ovarian, primary peritoneal, or fallopian tube cancer without a BRCA1/2 mutation. Patients had an Eastern Cooperative Oncology Group performance status of 0 or 1; approximately half had a PD-L1 combined positive score (CPS) of at least 10; and about 45% had received bevacizumab.
After one lead-in cycle of chemotherapy, patients were randomly assigned to one of three groups: pembrolizumab plus chemotherapy followed by maintenance pembrolizumab plus olaparib; pembrolizumab plus chemotherapy followed by maintenance pembrolizumab plus placebo; or placebo plus chemotherapy followed by placebo maintenance. Bevacizumab could be given at the investigator’s discretion.
Pembrolizumab was administered every 3 weeks for up to 35 cycles, and olaparib was given twice daily for up to 2 years. The primary endpoint was progression-free survival, tested first among patients with a PD-L1 CPS of at least 10 and then in the overall intention-to-treat population.
Key Findings
At the first interim analysis, after a median follow-up of 30.1 months, pembrolizumab plus chemotherapy followed by pembrolizumab/olaparib maintenance significantly reduced the risk of disease progression or death compared with the control regimen. Median progression-free survival was 23.7 vs 15.2 months among patients with a PD-L1 CPS of at least 10 (hazard ratio [HR] = 0.63; P < .0001) and 22.1 vs 14.6 months in the overall population (HR = 0.68; P < .0001).
The benefit was maintained at the final analysis after a median follow-up of 49.6 months. Median progression-free survival was 23.9 vs 15.2 months in the CPS ≥ 10 population (HR = 0.66) and 22.2 vs 14.6 months in the overall population (HR = 0.71). The benefit was generally consistent in prespecified subgroups, including according to whether patients received bevacizumab.
In contrast, pembrolizumab without olaparib did not significantly improve progression-free survival. Among patients with a CPS of at least 10, median progression-free survival was 17.3 months with pembrolizumab vs 15.2 months with the control regimen (HR = 0.95; P = .33). Because this comparison was not significant, progression-free survival was not formally tested in the overall population.
Neither experimental regimen improved overall survival. In the overall population, median overall survival was 47.7 months with pembrolizumab/olaparib, 44.2 months with pembrolizumab alone, and 47.1 months with the control regimen. The hazard ratio for death with pembrolizumab/olaparib vs the control regimen was 1.04.
The investigators cautioned against overinterpreting the difference between the positive progression-free survival result and the absence of an overall survival benefit. “We interpret the overall survival results cautiously,” they wrote, noting that progression-free survival may be the more reliable indicator of treatment benefit in this setting.
Grade 3 or higher treatment-related adverse events occurred in 66% of patients receiving pembrolizumab/olaparib, 56% receiving pembrolizumab alone, and 51% in the control group. The most common adverse events were neutropenia and anemia. Serious adverse events occurred in 24%, 21%, and 9% of patients, respectively. Treatment-related adverse events led to four deaths in the pembrolizumab/olaparib group and one in the pembrolizumab group. Global health status and quality of life did not differ meaningfully among the treatment groups at week 36.
Because pembrolizumab without olaparib did not improve progression-free survival, the investigators attributed the benefit to the PARP-containing maintenance strategy. “The observed benefit is from the PARP-containing maintenance strategy rather than from adding pembrolizumab to chemotherapy,” they wrote.
However, the trial could not determine how much pembrolizumab contributed beyond olaparib because the control regimen did not include a PARP inhibitor. The investigators said additional research is needed to define the regimen’s role relative to existing PARP inhibitor–based approaches, particularly for patients with homologous recombination deficiency–positive disease.
Dr. Vergote, of the Belgium and Luxembourg Gynaecological Oncology Group, University Hospitals Leuven, Leuven Cancer Institute, Belgium, is the corresponding author of the study.
DISCLOSURE: The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. Dr. Vergote reported consulting fees from multiple pharmaceutical companies, including Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.
