Berzosertib regimen extends PFS in ovarian cancer subset
The addition of berzosertib to gemcitabine extended PFS for women with platinum-resistant, high-grade serous ovarian cancer, according to results of a randomized phase 2 study published in The Lancet Oncology.
“[The results] suggest that ATR inhibition in combination with chemotherapy has the potential to offer significant benefits to patients with chemotherapy-resistant, high-grade serous ovarian cancer and, potentially, other tumor types where ATR plays a key role,” Panagiotis A. Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology at Dana-Farber Cancer Institute, said in a press release.
Women with high-grade serous ovarian cancers demonstrate increased replication stress, which renders cells vulnerable to ATR inhibitors due to the universal loss of the G1/S checkpoint, premature S phase entry, alterations of homologous recombination repair genes and expression of oncogenic drivers.
“The unbridled growth of cancer cells places enormous stress on the process of DNA replication,” Konstantinopoulos said. “ATR helps them survive that stress; its job is to coordinate the halting of the cell cycle to check if the DNA is intact or needs repair. Drugs that inhibit ATR — that deprive tumor cells of such repairs — have the potential to be particularly effective in some cancers.”
Konstantinopoulos and colleagues randomly assigned 70 women with recurrent, platinum-resistant, high-grade serous ovarian cancer to berzosertib (VE-822, Merck), a selective ATR inhibitor, in combination with gemcitabine (n = 34) or gemcitabine alone (n = 36) until disease progression or intolerable toxicity.
Women received 1,000 mg/m2 IV gemcitabine on days 1 and 8 with or without 210 mg/m2 IV berzosertib on days 2 and 9 of a 21-day cycle.
All women had an ECOG performance status of 0 or 1 and no more than one line of cytotoxic therapy in the platinum-resistant setting.
Investigator-assessed PFS served as the study’s primary endpoint.
Median follow-up was 53.2 weeks (interquartile range [IQR], 25.6-81.8) in the combination group and 43 weeks (IQR, 23.2-69.1) in the gemcitabine monotherapy group.
Results showed median PFS of 22.9 weeks (90% CI, 17.9-72) in the combination group and 14.7 weeks (90% CI, 9.7-36.7) for the gemcitabine monotherapy group (HR = 0.57; 90% CI, 0.33-0.98).
Twenty-four patients (71%) in the combination group and 29 patients (81%) in the gemcitabine monotherapy group died by the data cutoff date. Researchers reported median OS of 59.4 weeks vs. 43 weeks (HR = 0.84; 90% CI, 0.53-1.32).
Common treatment-related grade 3 or grade 4 adverse events included decreased neutrophil count (39% with gemcitabine alone vs. 47% with the combination) and decreased platelet count (6% vs. 24%).
Serious adverse events occurred among 28% of patients in the gemcitabine monotherapy group and 26% in the combination group. One patient in the gemcitabine monotherapy group died of sepsis and one patient in the combination group died of pneumonitis.
The study’s small sample size served as a limitation.
“This is the first randomized study of ATR inhibitor therapy in any tumor type, and the first suggesting a benefit of adding an ATR inhibitor to standard chemotherapy in ovarian cancer or any tumor type,” Konstantinopoulos and colleagues wrote. “Our results support future assessment of ATR inhibitor therapy in combination with gemcitabine in additional tumor types, especially in tumors that are predicted to have high replication stress.”