Investigation of the PORTOS gene expression signature and the benefit of docetaxel in the ECOG-ACRIN E3805 CHAARTED randomized trial.

Abstract

212 Background: The CHAARTED trial randomized men with metastatic hormone-sensitive prostate cancer (mHSPC) to either Androgen Deprivation Therapy (ADT) alone or with docetaxel. The trial showed an overall survival benefit, more so in patients with high-volume disease. We have previously developed a prostate cancer radiation response signature (PORTOS) which has been validated in multiple randomized trials. Given the similarities in DNA damage, we hypothesized that PORTOS might predict the benefit of docetaxel in CHAARTED. Methods: FFPE tumor samples from the trial were profiled using the commercial Decipher gene expression platform (N=160), and PORTOS was calculated as previously described, and was dichotomized into high/low based on the median, as scores exhibited a bi-modal distribution. Results: There were no significant associations with clinicopathologic variables (age, performance status, tumor volume, PSA, etc.). In patients with high PORTOS, there was a significant benefit for the addition of docetaxel for clinical progression (CP), castration resistance (CR), and overall survival (OS), which were not significant in the low PORTOS patients. The univariable interaction between PORTOS (as a continuous variable) and treatment arm was statistically significant for CP and trended towards significance for CR and OS. When accounting for clinicopathologic variables on a multivariable analysis, the interaction P-values were similar. The predictive effect of PORTOS was present only in the high-volume patients (N=125), where high PORTOS had a significant benefit for the addition of docetaxel for CP, CR, and OS. Conclusions: These results suggest that PORTOS could be used to identify which patients benefit from docetaxel added to ADT in mHSPC, and provides additional information even in high-volume patients. In the era of ADT + ARPIs for mHSPC, studies of PORTOS in cohorts with ADT + ARPI ± docetaxel will be critical in fully evaluating its clinical potential. Patients: All High Volume All PORTOS: High Low High Low PORTOS:Arm Interaction sHR P sHR P sHR P sHR P UVA P MVA P Clinical Progression 0.31 <0.001 0.61 0.11 0.31 <0.001 0.69 0.25 0.04 0.04 Castration Resistance 0.36 <0.001 0.61 0.07 0.36 <0.001 0.59 0.07 0.06 0.06 Overall Survival 0.58 0.05 0.66 0.2 0.50 0.03 0.61 0.14 0.07 0.14