Molecular and Genetic Determinants of Response to Carboplatin with or without an ATR Inhibitor (M6620) in mCRPC
Abstract
Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in clinical responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the response to a wide range of DNA damage and replication stress, and ATR inhibitors have been previously demonstrated in model systems to have synergistic activity with platinum compounds, and to have activity in homologous recombination (HR)-deficient cells rendered resistant to PARP inhibitors and cells deficient for ATM expression. Hypothesis/Objective: We hypothesize that the ATR inhibitor M6620 in combination with carboplatin will demonstrate clinical activity in mCRPC, both in HR-deficient patients (even with PARP inhibitor resistance) and potentially HR-proficient patients due to synergistic activity of M6620 with carboplatin related to induction of replication stress. I am leading NCI protocol # 10191, A Phase 2 study of M6620 with carboplatin compared to docetaxel with carboplatin in mCRPC (n=136 pts). This study mandates pre-treatment tumor biopsy and research blood collections for circulating cell-free DNA (cfDNA) analyses pre-treatment, every 3 cycles on treatment and at end of study. This proposal is for biomarker studies from these biospecimens and for functional studies in model systems to define genetic correlates of response and resistance to therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2022
- Accession Number
- AD1172668
Entities
People
- Atish D. Choudhury
- Kent W. Mouw
Organizations
- Dana–Farber Cancer Institute