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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

3753 - Circulating tumor DNA and RNA as an exploratory biomarker to evaluate GT0918 in a Phase 1/II clinical trial in mCRPC patients

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Tumour Site

Prostate Cancer

Presenters

Mengyao Tan

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

M. Tan1, S. Zhang1, Z. Zhao2, A. Wang3, D. Cheung3, P. Du4, J. Yu3, S. Jia3, C. Guo5, Y. Tong6, K. Zhou7

Author affiliations

  • 1 Translational Medicine, Predicine, Inc, 94545 - Hayward/US
  • 2 Research & Development, Predicine, Inc, 94545 - Hayward/US
  • 3 Clinical research, Predicine, Inc, 94545 - Hayward/US
  • 4 Bioinformatics, Predicine, Inc, 94545 - Hayward/US
  • 5 Research & Development, Suzhou Kintor Pharmaceuticals, Inc., 215000 - Suzhou/CN
  • 6 Business Development, Suzhou Kintor Pharmaceuticals, Inc., 215000 - Suzhou/CN
  • 7 Medical Oncology, Suzhou Kintor Pharmaceuticals, Inc., 215000 - Suzhou/CN
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Resources

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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