A Phase II Study of Berzosertib in Combination with Carboplatin Compared with Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

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 anticancer activity with platinum compounds in preclinical models. We therefore conducted a phase II study of the ATR inhibitor berzosertib + carboplatin versus docetaxel + carboplatin in metastatic castration-resistant prostate cancer (mCRPC). 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 and 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 and 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 (TrAE). 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 the planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair (HRR) deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM deficiency or high levels of phospho-Krüppel-associated box (KRAB) domain–associated protein 1 (pKAP1) detected in tissue were associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib + carboplatin demonstrated lower ORR and more frequent ≥ grade 3 TrAEs compared with docetaxel + carboplatin in this heavily pretreated, biomarker-unselected population. Significance: The combination of the ATR inhibitor berzosertib with carboplatin demonstrated a lower ORR compared with docetaxel with carboplatin in a heavily pretreated biomarker-unselected mCRPC population. Assays for HRR deficiency showed limited predictive capability, but a combined tissue biomarker of ATM deficiency and elevated pKAP1 (indicating elevated replication stress) was associated with benefit in both study arms and warrants investigation for benefit from carboplatin-based therapy.