Gemcitabine–Berzosertib Combo Beneficial for Recurrent, Platinum-Resistant Ovarian Cancer

Berzosertib plus gemcitabine yielded a benefit over gemcitabine alone in patients with platinum-resistant, high-grade ovarian cancer, according to results from a randomized phase 2 trial (Lancet Oncol. 2020 Jul. Epub ahead of print).

“High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms),” wrote Panagiotis Konstantinopoulos, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and co-investigators on the background of this trial.

Dr Konstantinopoulos et al hypothesized that combining berzosertib, an ATR inhibitor, with gemcitabine could show better efficacy and acceptable toxicity than gemcitabine alone.

Thus, 70 patients with recurrent, platinum-resistant, high-grade ovarian cancer and Eastern Cooperative Oncology Group performance status 0 or 1 were enrolled in this multi-center study.

These patients were randomly assigned to treatment with gemcitabine plus berzosertib (n = 34) or gemcitabine alone (n = 36) between February 2017 and September 2018.

The median follow-up time frame was 53.2 weeks in the gemcitabine plus berzosertib arm and 43.0 weeks in the gemcitabine arm. The median rate of progression-free survival was 22.9 weeks versus 14.7 weeks, respectively (hazard ratio, 0.57; 90% CI, 0.33-0.98).

Decreased neutrophil and platelets counts were the most common treatment-related grade 3 or 4 adverse events. Serious adverse events were observed in 9 (26%) patients in the gemcitabine plus berzosertib arm and 10 (28%) patients in the gemcitabine-alone arm.

There was 1 treatment-related death reported in each treatment arm, including one from pneumonitis in the gemcitabine plus berzosertib arm and sepsis in the gemcitabine arm.

According to Dr Konstantinopoulus and colleagues, this is the first randomized study of an ATR inhibitor in any tumor type.

“This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer,” they wrote, suggesting that further study of the combination is warranted.—Kaitlyn Manasterski