A phase II multicenter biomarker trial to study the predictive value of TMPRSS2-ERG before enzalutamide treatment in chemo-naïve metastatic castration-resistant prostate cancer.

Abstract

5040 Background: TMPRSS2-ERG fusion gene is a common driver of prostate cancer. The PREMIERE study is a phase II, single arm open-label, multicentre, clinical trial designed to analyse the predictive/prognostic value of TMPRSS2-ERG in first-line chemo-naïve mCRPC patients treated with enzalutamide. Methods: We centrally evaluated TMPRSS2-ERG in diagnostic samples using PCR, FISH and IHC for ERG. Among exploratory biomarkers we included plasma DNA, AR copy number by ddPCR and CTC by AdnaTest. PCWG2 criteria were used for outcome evaluation. We correlated TMPRSS2-ERGand other exploratory biomarkers with mCRPC outcomes. Results: Ninety eight patients with median age 77 y (range 59-95), ECOG 0/1 (54/46%) with mts located in bone (82%), LN (48%) and visceral (17%). With a median FU of 37.3 months, PSA response was PSA50: 82% and PSA90: 53%; median PSA-PFS was 13.7m (95%CI 10.2-19.0), Rad-PFS 26.7m (95%CI: 22.0-NA) and OS 37.5m (95%IC: 33.7-NA). TMPRSS2-ERG was detected in 32 pts (33%), AR gain in 11 pts and CTCs in 35 pts. No differences were observed based on TMPRSS2-ERG status for PSA response (PSA50: 81% vs 83%; p=0.8), PSA-PFS (median 12.8 vs 14.7m; HR 0.98; 95%CI 0.58-1.67; p=0.95), Rad-PFS (median 28.4 vs 26.4m; HR 1.02; 95% 0.53-1.96, p=0.95) or OS (median 36.9 vs 38.1m; HR 1.23; 95%CI 0.69-2.21, p=0.48). Plasma AR gain was associated with worse PSA-PFS (median 4.2 vs 14.7 m; p<0.0001), Rad-PFS (median 3.6 vs 28.4m; p<0.0001) and OS (median 12.7 vs 38.1m; p<0.0001). Plasma DNA and CTCs were also associated with worse outcome. Multivariate analyses of exploratory biomarkers are included in the table. Conclusions: The fusion gene TMPRSS2-ERG is not predictive nor prognostic on enzalutamide treatment in first-line chemo-naïve mCRPC patients. Plasma AR gain and CTCs are strong independent biomarkers associated with adverse outcome. Multivariate analysis of exploratory biomarkers. Clinical trial information: NCT02288936. [Table: see text]

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models

“…These data suggest the role of reduced ERG expression to significantly enhance the potency of NLG207. Interestingly, our findings show that camptothecin can decrease ERG mRNA expression in VCaP cells and another study implicates enhanced responses to enzalutamide associated with ERG expression in VCaP cells (55); despite the latter finding, recent data have suggested TMPRSS2-ERG to not be a predictive biomarker of enzalutamide efficacy in chemo-na€ ve patients with mCRPC in the first-line setting (56). Future investigations of ERG expression are necessary to better understand camptothecin sensitivity in prostate cancer cells and the role of TMPRSS2-ERG as a predictive biomarker of clinical outcomes following enzalutamide treatment.…”

Novel Therapeutic Approaches to Overcome Acquired Resistance to Enzalutamide in Patients with Advanced Prostate Cancer

“…51 In addition to the mRNA-based Adna-test platform, AR-V7 can also be detected via the EPIC sciences CTC-based platform, an immunofluorescencebased detection assay that measures AR-V7 protein localized in the nucleus. 52 The PROPHECY study evaluated the utility of the mRNA-and protein-based platforms, finding that both platforms were sufficient to detect AR-V7 and similarly show decreased PFS and OS following AAP/ENZA treatment. 53…”

“…Though ERG expression in VCaP cells has been implicated to enhance response to enzalutamide,51 clinical utility as a predictive biomarker has not been established. Recent data has suggested TMPRSS2-ERG to not be a predictive biomarker of enzalutamide efficacy in chemo-naïve patients with mCRPC in the first-line setting 52. Future investigations of ERG expression are necessary to better understand CPT sensitivity in prostate cancer cells and the role of TMPRSS2biosynthesis via study of 22Rv1 and VCaP cells in vitro and in vivo.53 Increased AR-V7 mRNA expression following combination treatment in comparison to NLG207 alone, as…”