Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial
Background: High-grade serous ovarian cancers show elevated replication stress, rendering cells susceptible to ATR inhibition due to near universal lack of the G1/S checkpoint (through unhealthy TP53 mutations), premature S phase entry (because of CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic motorists (through MYC amplification along with other mechanisms). We hypothesised the mixture of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior effectiveness to gemcitabine alone in high-grade serous ovarian cancer.
Methods: Within this multicentre, open-label, randomised, phase 2 study, 11 different centres in america Experimental Therapeutics Numerous Studies Network enrolled women (aged =18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of or 1, who’d limitless previous lines of cytotoxic therapy within the platinum-sensitive setting but a maximum of one type of cytotoxic therapy within the platinum-resistant setting. Qualified patients were at random assigned (1:1) to get intravenous gemcitabine (1000 mg/m2) on first day and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of the 21-day cycle until disease progression or intolerable toxicity. Randomisation ended centrally while using Theradex Interactive Web Response System, stratified by platinum-free interval, with a permuted block size six. Following central randomisation, patients and investigators weren’t masked to treatment assignment. The main endpoint was investigator-assessed progression-free survival, and analyses incorporated all patients who received a minumum of one dose from the study drugs. The research is registered with ClinicalTrials.gov, NCT02595892, and it is active but closed to enrolment.
Findings: Between February 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, who 70 were at random allotted to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). In the data cutoff date (February 21, 2020), the median follow-up was 53·2 days (25·6-81·8) within the gemcitabine plus berzosertib group and 43·0 days (IQR 23·2-69·1) within the gemcitabine alone group. Median progression-free survival was 22·9 days (17·9-72·0) for gemcitabine plus berzosertib and 14·7 days (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98 one-sided log-rank test p=0·044). The most typical treatment-related grade three or four adverse occasions were decreased neutrophil count (14 [39%] of 36 patients within the gemcitabine alone group versus 16 [47%] of 34 patients within the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] versus eight [24%]). Serious adverse occasions were noticed in ten (28%) patients within the gemcitabine alone group and nine (26%) patients within the gemcitabine plus berzosertib group. There is one treatment-related dying within the gemcitabine alone group because of sepsis and something treatment-related dying within the gemcitabine plus berzosertib group because of pneumonitis.
Interpretation: To the understanding, this is actually the first randomised study of the ATR inhibitor in almost any tumor type. This research shows an advantage of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This mixture warrants further analysis within this setting.