Mouw, Kent W

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Circulating tumor DNA (ctDNA) is increasingly being used to monitor minimal residual disease (MRD) in various solid tumors, including urothelial carcinoma (UC). It has emerged as a promising biomarker for MRD and may serve as a valuable tool to guide treatment decisions, particularly in patients at high risk of recurrence after definitive therapy or those experiencing favorable responses to systemic therapy in the setting of locally advanced or metastatic disease. ctDNA technology is largely agnostic to the type of tumor, which can be either hematologic or solid organ malignancies. Its clinical utility requires validation across different tumor types as ctDNA release kinetics and threshold values for testing often vary. Moreover, it is essential to evaluate ctDNA testing across a range of clinical scenarios, including screening, diagnosis, prognosis, and therapeutic decision making. The optimal frequency and duration of testing also need to be defined, particularly in settings such as postdefinitive therapy and ongoing chemotherapy for metastatic disease. In this study, we will summarize the current literature on the role of ctDNA in urothelial cancer. We will discuss the data that inform us of current clinical practice. Furthermore, we will explore evolving developments in the field from other tumor types and potential future directions in UC. Finally, we will highlight selected clinical scenarios for applications of ctDNA testing and its interpretation.