A Phase 2 Study of Berzosertib in Combination with Carboplatin compared to Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

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

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Journal
Cancer Research Communications
Published
2026-08-24
DOI
https://doi.org/10.1158/2767-9764.crc-26-0488
Primary Topic
DNA Repair Mechanisms
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article
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article

A Phase 2 Study of Berzosertib in Combination with Carboplatin compared to Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

Viktor A. Adalsteinsson, Edmund Folefac, David D. Yang, Mamta Parikh et al.
Cancer Research Communications
DNA Repair Mechanisms
article

A Phase 2 Study of Berzosertib in Combination with Carboplatin compared to Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

Viktor A. Adalsteinsson, Edmund Folefac, David D. Yang, Mamta Parikh, Daniel Lee, Li Chen, Caiwei Zhong, Peter I-Fan Wu, Irbaz Bin Riaz, Mary‐Ellen Taplin, David Johnson Einstein, Eliezer M. Van Allen, Charles A. Kunos, Elizabeth Riley Kessler, Alan D. D’Andrea, Amanda F. Pace, Geoffrey Ira Shapiro, Rana R. McKay, Wanling Xie, Ruolin Liu, Kent W. Mouw, Atish D. Choudhury, Tina Mayer, Bose Kochupurakkal, Biswajit Das, Steven D. Gore
article en

Abstract

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

Cancer Research Communications
Rutgers, The State University of New Jersey (US), Broad Institute (US), Beth Israel Deaconess Medical Center (US), University of Pittsburgh (US), National Foundation for Cancer Research (US), Markey Cancer Center (US), The Ohio State University Wexner Medical Center (US), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), Mayo Clinic Hospital (US), Frederick National Laboratory for Cancer Research (US), University of Colorado Cancer Center (US), National Cancer Institute (MY), National Cancer Institute (US), University of California, Davis (US), University of Colorado Denver (US)
Good health and well-being
Openalex Percentile: Top 16%
DNA Repair Mechanisms
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