In a phase II trial reported in JAMA Oncology, Sumanta K. Pal, MD, FASCO, and colleagues found that the addition of the ATR inhibitor berzosertib to cisplatin/gemcitabine provided no benefit in patients with metastatic urothelial carcinoma. The triplet did not prolong progression-free survival, and a trend toward inferior survival was observed; additionally, the combination was associated with significantly higher rates of hematologic toxicities.
As stated by the investigators, “Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents.”
Sumanta K. Pal, MD, FASCO
Study Details
The open-label trial included 87 patients from National Cancer Institute Experimental Therapeutics Clinical Trials Network centers who had received no prior cytotoxic therapy for metastatic disease and were at least 12 months removed from their last treatment with perioperative therapy. Patients were randomly assigned between January 2017 and December 2020 to receive berzosertib at 90 mg/m2 on days 2 and 9 plus cisplatin at 60 mg/m2 on day 1 and gemcitabine at 875 mg/m2 on days 1 and 8 of 21-day cycles (n = 46) or cisplatin at 70 mg/m2 on day 1 and gemcitabine at 1,000 mg/m2 on days 1 and 8 of 21-day cycles (n = 41) for up to six cycles. The primary endpoint was progression-free survival.
Progression-Free Survival
At data cutoff (December 2020), median follow-up was 18.9 months (interquartile range = 9.9–27.4 months). Median progression-free survival was 8.0 months (95% confidence interval [CI] = 6.0–14.4 months) in the berzosertib group vs 8.0 months (95% CI = 6.8 months–not estimable) in the control group (unadjusted hazard ratio [HR] = 1.17, 95% CI = 0.69–1.98, P = .55; Bajorin risk-adjusted HR = 1.22, 95% CI = 0.72–2.08).
Median overall survival was 14.4 months (95% CI = 10.0 months–not estimable) in the berzosertib group vs 19.8 months (95% CI = 14.8 months–not estimable) in the control group (unadjusted HR = 1.33, 95% CI = 0.71–2.48, P = .37; Bajorin risk-adjusted HR = 1.42, 95% CI = 0.76–2.68). Objective response was observed in 54% vs 63% of patients (P = .51), with complete response seen in 9% vs 10%.
KEY POINTS
- Median progression-free survival was 8.0 months in the berzosertib group vs 8.0 months in the control group.
- Patients in the berzosertib group had a greater incidence of hematologic toxicity and received a significantly lower median dose of cisplatin.
Adverse Events
Grade 3 to 4 adverse events occurred in 91% of patients in the berzosertib group vs 66% of the control group (P < .01), including higher rates of thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%). The higher rates of severe hematologic events were associated with more dose reductions in the berzosertib group; median cisplatin doses were 250 mg/m2 vs 370 mg/m2 (P < .001), representing 69% vs 88% of planned dosing. Adverse events led to death in one patient in the berzosertib group (due to cardiac arrest) and one patient in the control group (due to multiorgan failure).
The investigators concluded: “The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine.”
Dr. Pal, of City of Hope Comprehensive Cancer Center, is the corresponding author for the JAMA Oncology article.
Disclosure: This study was supported by the grants from the National Cancer Institute (NCI) and by Merck KGaA through a Cooperative Research and Development Agreement with NCI. For full disclosures of the study authors, visit jamanetwork.com.
