Abstract 3753
Background
Metastatic castration resistant prostate cancer (mCRPC) is a complex disease with distinct molecular features in relation to genomic instability and selective treatment pressure. Circulating tumor DNA and RNA fragments (ctDNA & ctRNA) found in blood offers the potential of disease diagnosis, monitoring and resistance mechanism interrogation by detecting genomic alterations from tumor. We explored ctDNA & ctRNA-based biomarkers from patient blood to assess their associations with clinical response of GT0918, a potent AR antagonist, in a Phase 1/2 clincal study in mCRPC who progressed after abiraterone or enzalutamide and docetaxol, or cannot tolerate either or both therapies.
Methods
We performed a retrospective analysis of blood samples from mCRPC patients collected at baseline, on- and after study during the trial. A highly sensitive ctDNA- & ctRNA-based NGS assay was developed to detect mutation, copy number gain, fusion and splicing variants. Statistical analyses were performed in R.
Results
20 blood samples were collected at multiple time points from 8 patients. CtDNA-based variants are detected in all of patients. The most frequent mutations are TP53 (55.0%) and AR (30.0%). Combined mutation rates in PTEN-PI3K-AKT and DNA damage repair pathways (BRCA1/BRCA2/ATM) are both 35.0%. Importantly, AR hotspot mutations (W742C, T878A, and S889G) and amplifications are detected in 4 subjects. AR splicing variants (AR-V3, AR-V7) were found in 3 patients by ctRNA assay. Interestingly, one AR-V3+ patient became negative during the treatment accompanied by a decrease of other molecular biomarkers including prostate-specific SPOP mutation and cfDNA yield. In contrast, another patient who was AR-V3+ at C4D1, had constantly high AR amplification and increasing cfDNA yields over treatment. Last, as a hallmark of prostate cancer, TMPRSS2-ERG fusion was also detected in 2 patients.
Conclusions
This is a preliminary study to explore genomic alterations in mCRPC in response to GT0918 treatment. As a non-invasive assay, the ctDNA & ctRNA-based assay was highly sensitive and provided useful molecular insights for monitoring treatment effect and deciphering drug sensitivity & resistance mechanisms.
Clinical trial identification
NCT02826772.
Legal entity responsible for the study
Suzhou Kintor Pharmaceuticals, Inc.
Funding
Suzhou Kintor Pharmaceuticals, Inc.
Editorial Acknowledgement
Disclosure
M. Tan, S. Zhang, Z. Zhao, A. Wang, D. Cheung, P. Du, J. Yu: Sockholder: Predicine, Inc. S. Jia: CEO and stockholder: Predicine, Inc. C. Guo, Y. Tong, K. Zhou: Stockholder: Suzhou Kintor Pharmaceutials, Inc.
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