Cisplatin Plus Gemcitabine Demonstrates Superiority Over Cisplatin/Gemcitabine Plus Berzosertib in Metastatic Urothelial Carcinoma

Patients with metastatic urothelial carcinoma did not derive further benefit from the addition of berzosertib to cisplatin and gemcitabine.

Treatment with cisplatin and gemcitabine appears to be more efficacious than berzosertib, cisplatin, and gemcitabine in patients with metastatic urothelial carcinoma, according to the results of a phase 2 study (NCT02567409) published in JAMA Oncology.

After a median follow up of 18.9 months (Interquartile range [IQR], 9.9-27.4), all patients had discontinued the study treatment. Investigators reported that the median progression-free survival (PFS) was 8.0 months (95% CI, 6.8–not assessable [NA]) in the cisplatin/gemcitabine arm vs 8.0 months (95% CI, 6.0-14.4) in the berzosertib, cisplatin, and gemcitabine arm (unadjusted HR, 1.17; 95% CI, 0.69-1.98; P = .55). Moreover, patients in the control group had a longer median overall survival (OS) of 19.8 months (95% CI, 14.8-NA) compared with 14.4 months (95% CI, 10.0-NA) in the berzosertib arm (unadjusted HR, 1.33; 95% CI, 0.71-2.48; P = .37).

“Our study showed no improvement in PFS or RR with the addition of berzosertib to cisplatin and gemcitabine in patients with [metastatic urothelial cancer]. Of concern, a trend toward inferior survival was noted with the addition of berzosertib. In addition, significantly higher rates of high-grade adverse effects (primarily hematologic) were noted in patients receiving berzosertib. These results are unexpected given the synergy between chemotherapy and berzosertib demonstrated across preclinical studies, as previously noted,” investigators wrote.

The open label, randomized clinical trial took place across 23 centers. Patients who were 18 years or older with measurable histologically- or cytologically-confirmed metastatic urothelial carcinoma were eligible to enroll on the study. Additionally, it was required that patients have not undergone treatment with cytotoxic chemotherapy for their metastatic disease and have waited at least 12 months since receiving platinum-based chemotherapy.

Patients were randomized 1:1 to be treated with either cisplatin and gemcitabine, or cisplatin and gemcitabine plus berzosertib. Those who enrolled were stratified based on Bajorin risk category. Patients in the control group received 70 mg/m2 of cisplatin on day 1 plus 1000 mg/m2 of gemcitabine on days 1 and 8 of a 21-day cycle. Moreover, the experimental arm received 60 mg/m2 of cisplatin on day 1, 875 mg/m2 of gemcitabine on days 1 and 8, and 90 mg/m2 of berzosertib on days 2 and 9 of a 21-day cycle.

From January 27, 2017, to December 12, 2019, investigators enrolled 91 patients on the clinical trial. A total of 41 patients were randomized to the control group, as well as 46 to the experimental group. Most patients were male (78%), and White (85%).

Additional findings from the study indicated that the median duration of therapy was 3.9 months (IQR, 2.3-4.2) in the control group vs 3.7 months (IQR, 2.0-4.3) in the berzosertib group. Investigators also reported an overall response rate (ORR) of 63% (95% CI, 0.47-0.78) in the control groups, including a complete response (CR) rate of 9.8%. Moreover, the experimental arm had an ORR of 54%, including a CR rate of 8.7%. The difference in ORR between the 2 arms was not considered significant (P = .51).

Two grade 5 adverse effects (AEs) were reported that were unrelated to disease progression, including cardiac arrest in the experimental arm and multiorgan failure in the control arm. The incidence of grade 3/4 AEs were higher with the triplet regimen (91%) vs the doublet regimen (66%; P <.01). Notable differences were observed regarding hematologic AEs, with grade 3/4 thrombocytopenia occurring in 59% of those in the experimental arm vs 39% in the control arm. Additionally, grade 3/4 neutropenia was higher in the triplet cohort (37%) vs the doublet cohort (27%).

Investigators also reported that 35% of patients in the experimental cohort required dose reductions for cisplatin, as well as 61% for gemcitabine and 20% for berzosertib. Additionally, 34% of those in the placebo cohort needed dose reductions for cisplatin and 54% required dose reductions for gemcitabine.

“A lesson derived from this trial is that excessive attenuation of cisplatin dosing should be avoided whenever feasible,” investigators concluded.


Pal SK, Frankel PH, Mortazavi A, et al. Effect of cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma a phase 2 randomized clinical trial. JAMA Oncol. Published online August 26, 2021. doi:10.1001/jamaoncol.2021.3441