ASCO 2021: A Randomized Phase II Study Comparing Cisplatin and Gemcitabine with or Without Berzosertib in Patients with Advanced Urothelial Carcinoma

( Cisplatin and gemcitabine is a first line chemotherapy option for patients with metastatic urothelial carcinoma who are medically eligible to receive cisplatin. These chemotherapies induced DNA damage through distinct mechanisms, and it stands to reason that further disruption of DNA break repair may augment the efficacy of these agents. As the ATR (ataxia telangiectasia and Rad3-related) gene responds to DNA single-strand breaks, inhibiting this protein may provide additional benefit to patients. Dr. Pal and colleagues tested such an approach in a randomized phase 2 study of cisplatin and gemcitabine with or without the ATR inhibitor berzosertib.

Berzosertib is an ATR inhibitor with preclinical data suggestive of increased anti-tumor activity when added to cisplatin and gemcitabine. Phase 1 data has supported the feasibility of this triple-drug combination. To further evaluate this combination, the following trial schema was designed. Patients with measurable metastatic urothelial carcinoma who were medically eligible for cisplatin and had not received prior chemotherapy for metastatic disease or were at least 12-months post neoadjuvant chemotherapy were eligible. Patients were randomized to standard of care dosing of cisplatin and gemcitabine or dose reduced cisplatin and gemcitabine with berzosertib dosed 24 hours after chemotherapy. Patients were stratified by the Bajorin risk group, and treatment was continued for up to 6 cycles on each study arm.


The primary objective of the study was to assess whether berzosertib improves the progression free survival of patients treated with cisplatin and gemcitabine. The median PFS of the control arm was estimated at 5.3 months, and the study had 90% power to detect an improvement in median PFS to 10.1 months with the addition of berzosertib if 80 evaluable patients were enrolled, using a 1-sided alpha of 0.1. A pre-specific interim analysis occurred after 40 patients were enrolled with stopping rules in place for futility. A total of 87 patients were randomized, 41 to the control arm and 46 to the study arm. The characteristics of these patients are shown below.


The study did not meet its primary endpoint of improved progression free survival with berzosertib, with the median PFS in both arms measured at approximately 8 months.


The median overall survival was longer for patients in the control arm at 19.8 months versus 14.4 months in the combination berzosertib/chemotherapy study arm. No statistically significant differences were detected in study arm effects by age, gender, performance status or Bajorin risk group.   Toxicity data was notable for more grade 3 and grade 4 thrombocytopenia and neutropenia, as well as more grade 3 anemia and leukopenia in the control arm. Almost 20% of patients in the study arm required dose reduction of berzosertib, and more patients required growth factor support in the study arm. Furthermore, patients who received berzosertib received a statistically significant lower median cisplatin cumulative dose (250 mg/m2) relative to the median cumulative dose for patients on the control arm (370 mg/m2)

Dr. Pal concluded his talk by highlighting that the addition of berzosertib did not prolong progression free survival for cisplatin and gemcitabine in metastatic urothelial carcinoma, cause more hematologic toxicities, and attenuated the doses of chemotherapy that were delivered potentially explaining the numerically inferior overall survival in the study arm.

Presented by: Sumanta Kumar Pal, MD, Associate Professor, Department of Medical Oncology and Therapeutics Research, Co-Director, Kidney Cancer Program, City of Hope

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021