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Addition of an ATR Inhibitor to Gemcitabine in Platinum-Resistant High-Grade Serous Ovarian Cancer


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As reported in The Lancet Oncology by Panagiotis A. Konstantinopoulos, MD, and colleagues, a 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.

Panagiotis A. Konstantinopoulos, MD

Panagiotis A. Konstantinopoulos, MD

Study Details

In the open-label trial, 70 patients from 11 sites in the United States 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. Patients could have 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. Overall, platinum-free interval was ≤ 3 months in 37% of patients and > 3 to < 6 months in 63%. Most patients (54%) had received two prior lines of therapy (range = 1–8). The primary endpoint was investigator-assessed progression-free survival.

Progression-Free Survival

At data cutoff, median follow-up was 53.2 weeks in the berzosertib/gemcitabine group and 43.0 weeks in the gemcitabine alone group. Median progression-free survival was 22.9 weeks (90% confidence interval [CI] = 17.9–72.0) in the doublet group vs 14.7 weeks (90% CI = 9.7–36.7) in the gemcitabine alone group (hazard ratio [HR] = 0.57, 90% CI = 0.33–0.98, P = .044). 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 and 18.6 weeks vs 15.3 weeks (HR = 1.04, P = .46) among those with a platinum-free interval of > 3 to < 6 months.

Objective response was observed in 3% vs 11% of patients. Median overall survival was 59.4 weeks vs 43.0 weeks among all patients (HR = 0.84, P = .26); median overall survival was 84.4 weeks vs 40.4 weeks (HR = 0.42, P = .034) among patients with a platinum-free interval of ≤ 3 months and 39.0 weeks vs 59.9 weeks (HR = 1.29, P = .23) among those with platinum-free interval of > 3 months.

Adverse Events

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% vs 28% of patients. Adverse events led to discontinuation of treatment in 18% vs 11%. Treatment-related death occurred in one patient in the berzosertib/gemcitabine group (due to pneumonitis) and one patient in the gemcitabine alone group (due to sepsis).

The investigators concluded, “To our knowledge, 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. This combination warrants further investigation in this setting.”

Dr. Konstantinopoulos, of the Department of Medical Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.


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