Works well under stress.

ATR kinase is an important cellular protein that, in response to DNA damage or stress, activates cell cycle arrest and downstream DNA repair mechanisms. And cancer cells aren’t short on replicative stress. This randomized phase 2 study explored the efficacy of gemcitabine +/- the ATR inhibitor berzosertib in 88 patients with platinum-refractory (including prior PARP-inhibitor maintenance) high-grade serous ovarian cancer. Berzosertib was administered 24 hours after each gemcitabine dose because, in preclinical studies, this was when berzosertib was maximally effective due to cells accumulating in S-phase with maximal ATR activity. Median progression free survival (PFS) was greater with the addition of berzosertib (15→ 23 weeks). This appeared driven by patients with a <3 month platinum-free interval (~one-third of participants) for whom median PFS improved from 9 → 28 weeks and median overall survival from 40 → 84 weeks. TBL: Administering the ATR inhibitor berzosertib in the setting of gemcitabine-induced DNA replicative stress improves progression-free survival for platinum-refractory ovarian cancer. | Konstantinopoulos, Lancet Oncol 2020