Extended Follow-Up Report of a Randomized Phase II Trial Comparing Gemcitabine and Cisplatin with or Without Berzosertib in Patients with Advanced Urothelial Carcinoma.

614 Background: Gemcitabine with cisplatin (GC) remains a frontline treatment option for patients (pts) with metastatic urothelial cancer (mUC). Preclinical synergy has been noted when combining cisplatin with berzosertib, a selective ATR inhibitor. This trial sought to determine the effect of addition of berzosertib to GC on clinical outcomes in mUC; here we present final study results with extended follow-up. Methods: This open-label, randomized study enrolled pts with confirmed mUC, no prior cytotoxic therapy for metastatic disease, > 12 months since perioperative chemotherapy and eligible for cisplatin based on standard criteria. Pts were randomized to receive either GC plus berzosertib (Arm A) or GC alone (Arm B). In Arm A, cisplatin 60 mg/m 2 IV was given on D1, gemcitabine 875 mg/m 2 IV on D1 & 8, and berzosertib 90 mg/m 2 IV on D2 & 9 of a 21-day cycle. In Arm B, cisplatin 70 mg/m 2 IV was given on Day 1 (D1) and gemcitabine 1000 mg/m 2 IV on D1 & 8 of a 21-day cycle. The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints including response rate (RR), overall survival (OS) and toxicity. Results: A total of 87 pts (median age 67; M:F 68:19) were randomized, 46 pts to Arm A and 41 pts to Arm B. With a median follow-up of 37.7 months (95% CI: 28.3, 39.3), median PFS in Arm A was 6.2 month and 7.1 months in Arm B (HR: 1.3 [95% CI: 0.8-2.2], p=0.1). RR was 54% in Arm A and 63% in Arm B. Median OS was 10.9 months in Arm A and 19.8 months in Arm B (HR: 1.2 [95% CI: 0.7-2.1], p=0.2). Common > Grade 3 adverse events included anemia (Arm A: 57%, Arm B: 24%), neutropenia (Arm A: 36.9%, Arm B: 26.8%), thrombocytopenia (Arm A: 58.7%, Arm B: 39%). Conclusions: With >18 months of extended follow-up, there remained no PFS or OS benefit with the addition of berzosertib to GC, compared to GC alone in a biomarker unselected population. Myelosuppression was common despite reduced dosing of cisplatin and gemcitabine suggesting that combining ATR inhibition with platinum-based chemotherapy may not be feasible in pts with mUC. Clinical trial information: NCT02567409 .