(UroToday.com) In this study, Atish Choudhury and colleagues present the rationale and design for a phase 2 study of M6620, an inhibitor of the ATR kinase, in combination with carboplatin for patients with metastatic castration-resistant prostate cancer (mCRPC).
ATR is a kinase that is activated by single-stranded DNA that is coated with the replication protein A and is capable of helping repair a wide range of DNA damage or replication programs. This is in contrast with the ATM protein, which is predominantly involved in repair of double-stranded DNA breaks. In preclinical models, inhibition of the ATR kinase is effective in cells that have lost ATM expression or are resistant to PARP inhibitors. Carboplatin chemotherapy induces replicative stress via intra- and inter-strand crosslinking. The rationale for this study is that further inhibiting the ability of a cancer cell to repair carboplatin induced DNA by utilizing M6620 will lead to synergistic cancer cell death.
The outline of this study is shown below. Patients will be randomized, regardless of homologous recombination repair deficiency status, to either carboplatin + docetaxel or carboplatin + M6620. The primary endpoint is difference in PSA response rate (> 50%) or radiographic response by RECIST 1.1. Secondary objectives include time to PSA progression, radiographic progression, safety, and biomarker studies to associate DNA-damage repair status and response. 
Patients with mCRPC with measurable disease (either PSA > 2 or radiographic by RECIST 1.1) who have progressed on prior taxane and at least one androgen-receptor inhibitor will be eligible for the study. Patients who have previously received platinum agents or are taking potent effectors of CYP3A4 are not eligible.
Planned biomarker studies include whole-exome sequencing to assess for mutations in DNA-damage repair genes as well as mutational signatures that reflect homologous recombination deficiency. Immunohistochemistry will be performed for RAD51 focus formation, ATM status, and phospho-KAP1 as a readout of DNA damage. Finally, circulating tumor DNA will also be sequenced using ultra-low pass whole genome sequencing.
In total, this trial proposes the novel approach of ATR inhibition with carboplatin as a treatment for advanced mCRPC and incorporates relevant biomarkers to identify mechanisms of response and resistance.
Presented by: Atish D. Choudhury, MD, PhD, Senior Physician and Instructor in Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.