Dehydroepiandrosterone in metastatic castration-resistant prostate cancer: Preliminary results from the SU2C-PCF West Coast Dream Team (WCDT).

Abstract

179 Background: Aberrant androgen receptor (AR) phenotypes (e.g. splice variants, amplification) are strongly correlated with abiraterone (Abi) and enzalutamide (Enz) resistance. Low serum dehydroepiandrosterone (DHEA) is also associated with poor outcomes to AR-targeted therapy. Here, we investigate the relationship between serum DHEA, AR phenotype, and treatment efficacy in the WCDT. Methods: Patients (pts) with progressive mCRPC enrolled to the WCDT from UCSF, OHSU, UCLA, UBC, and UCD were included in this analysis. Serum DHEA was analyzed via high-pressure liquid chromatography and tandem mass spectrometry. Limit of quantitation (LQ) of DHEA was 0.2ng/mL. Full-length AR (AR-FL) and AR-v7 expression, obtained via RNAseq of metastatic tumor biopsies, was expressed as total reads mapped to gene. PSA response (PSAr) was defined as ≥ 50% PSA decline. Results: 35 pts were included in this analysis: 15 had treatment-naïve mCRPC, and 20 had prior AR-targeted therapy (14 Abi, 6 Enz). All pts were docetaxel-naïve. 11 pts had DHEA < LQ; of these, 10 had received prior AR-targeted therapy. 12 pts received subsequent chemotherapy, and 23 received subsequent Abi/Enz (7 Abi, 16 Enz). In pts with DHEA < LQ, 4/5 (80%) chemotherapy-treated pts had PSAr, while 1/6 (17%) Abi/Enz-treated pts had PSAr. In pts with DHEA ≥ LQ, 2/7 (27%) chemotherapy-treated pts had PSAr, while 9/16 (56%) Abi/Enz-treated pts had PSAr. The relationship between DHEA and PSAr was significantly different between the treatment groups (p = 0.0285). DHEA was higher in patients with PSAr to Abi/Enz versus those without PSAr (median, 0.871 versus 0.275ng/mL, p = 0.006). In an analysis of 27 pts with RNAseq data, the AR-v7/AR-FL ratio was significantly higher in those with DHEA < LQ (median ratio 8.91, versus 3.38 in DHEA ≥ LQ, p = 0.032). Conclusions: In this exploratory analysis, there is a significant difference in the relationship between DHEA and PSAr in chemotherapy- versus Abi/Enz-treated patients. DHEA < LQ was also associated with a higher AR-v7/AR-FL ratio, a potential avenue for further exploration of tumor biology. These results support a larger study to evaluate DHEA as a potential biomarker in mCRPC. Clinical trial information: NCT02432001.