358 - Validation of Six Androgen Production, Uptake and Conversion Genes (APUC-6) in the ECOG-ACRIN E3805 CHAARTED Prostate Cancer Trial
Presenter(s)
X. Shi1, A. C. Shetty1, J. Wang2, Y. Song1, P. Sutera3, M. P. Deek4, R. Phillips5, C. Tang6, J. Proudfoot7, E. Davicioni8, P. L. Nguyen9, C. Sweeney10, E. Boytim11, C. J. Ryan12, E. Antonarakis11, J. Hwang11, and P. T. Tran1; 1University of Maryland School of Medicine, Baltimore, MD, 2Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 3University of Rochester, Rochester, NY, 4Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 5Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 6Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 7Decipher Biosciences, Vancouver, Canada, 8Veracyte Inc., San Diego, CA, 9Department of Radiation Oncology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, 10South Australian Immunogenomics Cancer Institute, Adelaide, Australia, 11University of Minnesota, Minneapolis, MN, 12Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s): Metastatic prostate cancer (mPC) remains incurable. Persistent androgen receptor (AR) activation promotes tumor progression and metastasis and impacts patient survival. A group of six genes (HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, CYP17A1) involved in androgen production, uptake, and conversion (APUC-6) has been identified that may define a subset of mPC with distinct clinical outcomes. We investigated the association of APUC-6 with outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and ability to predict therapeutic responses.
Materials/Methods: We analyzed APUC-6 and AR expression from the phase 3 ECOG-ACRIN E3805 CHAARTED trial (n=160). Patients were stratified into four subgroups based on APUC-6 and AR gene expression: APUC-6 high/AR low (n=34), APUC-6 high/AR high (n=6), APUC-6 low/AR low (n=86) and APUC-6 low/AR high (n=34). We compared key clinical outcomes including progression-free survival (PFS), time-to-castration resistance (ttCR) and overall survival (OS) across these subgroups within the two treatment arms: androgen deprivation therapy (ADT) alone versus (vs.) docetaxel + ADT (D-ADT) to assess APUC-6/AR as a prognostic biomarker. Interaction analysis was conducted between treatment arms and subgroups.
Results:
Standard clinicopathologic factors were balanced across subgroups, except lower Gleason score =8 in APUC-6 high/AR low patients. APUC-6 high/AR low expression showed significantly improved PFS (median 47.3 months, p<0.0001), ttCR (median 17.3 months, p=0.0011) and OS (median 58.1 months, p<0.0001) compared to other subgroups even within synchronous high-volume disease (median PFS 23.1 months, p=0.0022; median ttCR 14.9 months, p=0.021; median OS 57.6 months, p=0.00038). No difference in PFS, ttCR and OS were observed in the APUC-6 high/AR low subgroup between ADT alone and D-ADT treatment arms. In contrast, APUC-6 low/AR low subgroup had improved outcomes with the addition of docetaxel to ADT, median PFS 34.9 vs. 15.0 months (HR 0.37, Cl 0.21-0.65, p=0.00036), median ttCR of 22.8 vs. 6.4 months (HR 0.38, Cl 0.23-0.64, p=0.00017) and median OS 69.5 vs. 29.8 months (HR 0.39, Cl 0.21-0.72, p=0.0019) compared to ADT alone with interaction p-value 0.0004 for PFS, 0.0001 for ttCR, and 0.0010 for OS.Conclusion:
APUC-6 high/AR low subgroup exhibited favorable PFS, ttCR and OS outcome, with these survival benefits persisting in patients with synchronous high-volume disease. Notably, interaction analysis revealed that patients with APUC-6 low/AR low expression derived significant benefits from the addition of docetaxel to ADT, as evidence by improved in PFS, ttCR and OS. These APUC-6 data from the CHAARTED trial need to be validated in other mPC trials and disease contexts such as localized prostate cancer.