As reported in The Lancet Oncology by Panagiotis A. Konstantinopoulos, MD, Dana-Farber Cancer Institute, and colleagues, a U.S. Experimental Therapeutics Clinical Trials Network phase II trial has shown significantly prolonged progression-free survival with the addition of the ATR (ataxia telangiectasia and Rad3-related) kinase inhibitor berzosertib to gemcitabine in women with recurrent platinum-resistant high-grade serous ovarian cancer.1 The benefit of the combination was greatest in patients with a platinum-free interval of 3 months or less.
Panagiotis A. Konstantinopoulos, MD
As stated by the investigators, “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). We hypothesized that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.”
In the open-label trial, 70 patients from 11 U.S. sites were randomly assigned between February 2017 and September 2018 to receive gemcitabine at 1,000 mg/m2 on day 1 and day 8 plus intravenous berzosertib at 210 mg/m2 on day 2 and day 9 of 21-day cycles (n = 34) or gemcitabine alone (n = 36) until disease progression or intolerable toxicity. Randomization was stratified by a platinum-free interval. Patients could have had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Crossover from the gemcitabine group to the gemcitabine/berzosertib group was permitted for patients with disease progression. The primary endpoint was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1.
Overall, the platinum-free interval was 3 months or less in 38% of patients in the berzosertib/gemcitabine groupvs 36% in the gemcitabine group and between 3 and 6 months in 62% vs 64%. For the berzosertib/gemcitabine vs gemcitabine groups, 88% vs 94% of patients were White, and Eastern Cooperative Oncology Group performance status was 0 or 1 in all patients. Disease stage was III in 53% vs 44% and IV in 26% vs 39%. Overall, 68% vs 78% had received one or two (59% vs 50%) prior lines of therapy (range = 1–8); 41% vs 31% had received one prior line of therapy in the platinum-resistant setting; 32% vs 19% had received prior PARP inhibitor therapy; 29% vs 25% had received prior antiangiogenic therapy; and 18% vs 14% had BRCA-mutant disease.
At the data cutoff, median follow-up was at 53.2 weeks in the berzosertib/gemcitabine group and at 43.0 weeks in the gemcitabine group. Median progression-free survival was 22.9 weeks (90% confidence interval [CI] = 17.9–72.0 weeks) in the berzosertib/gemcitabine group vs 14.7 weeks (90% CI = 9.7–36.7 weeks) in the gemcitabine group (hazard ratio [HR] = 0.57, 90% CI = 0.33–0.98, P = .044), with 6-month rates of 50% vs 36%. Median progression-free survival was 27.7 weeks vs 9.0 weeks (HR = 0.29, P = .0087) among patients with a platinum-free interval of 3 months or less and 18.6 weeks vs 15.3 weeks (HR = 1.04, P = .46) among those with a platinum-free interval of between 3 and 6 months.
An objective response was observed in 3% (one patient; response duration = 7 weeks) vs 11% (four patients; response durations = 6–27 weeks) of patients. Clinical benefit (defined as an objective response or stable disease for at least 4 months) was observed in 35% vs 25%, with rates of 54% vs 23% in patients with a platinum-free interval of 3 months or less and 24% vs 26% in those with an interval of more than 3 months.
A total of 15 patients in the gemcitabine group crossed over to berzosertib/gemcitabine after disease progression. Median overall survival was 59.4 weeks vs 43.0 weeks among all patients (HR = 0.84, P = .26), including median durations of 84.4 weeks vs 40.4 weeks (HR = 0.42, P = .034) among patients with a platinum-free interval of 3 months or less and 39.0 weeks vs 59.9 weeks (HR = 1.29, P = .23) among those with a platinum-free interval of more than 3 months.
The most common treatment-related grade 3 or 4 adverse events in the berzosertib/gemcitabine group were decreased neutrophil count (47% vs 39% in the gemcitabine group), decreased platelet count (24% vs 6%), and anemia (15% vs 11%). Serious adverse events were observed in 26% (thrombocytopenia in 12%) vs 28% of patients (fever or febrile neutropenia in 6%). Adverse events led to discontinuation of treatment in 18% (due to fatigue in two patients, pneumonitis in two patents, and abdominal pain and small bowel obstruction in one patient each) vs 11% of patients (due to neutropenia, capillary leak syndrome, edema, and acute renal failure in one patient each). Treatment-related death occurred in one patient in the berzosertib/gemcitabine group (due to pneumonitis) and one patient in the gemcitabine group (due to sepsis).
The investigators concluded: “To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting.”
DISCLOSURE: The study was funded by the National Cancer Institute. Dr. Konstantinopoulos has served in a consulting or advisory role for Alkermes, AstraZeneca, Bayer, Merck, Pfizer/EMD Serono, Tesaro, and Vertex; and has received institutional research funding from AstraZeneca, Lilly, Merck, Merck Serono, Pfizer, and Tesaro.
1. Konstantinopoulos PA, Cheng S-C, Hendrickson AEW, et al: Berzosertib plus gemcitabine vs gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: A multicentre, open-label, randomised, phase II trial. Lancet Oncol 21:957-968, 2020.