Early responses to enzalutamide in AR-V7 positive first line metastatic castration-resistant prostate cancer (mCRPC). A prospective SOGUG clinical trial: The PREMIERE study

Background

AR-V7 has been proposed as a biomarker for early resistance to enzalutamide in heavily pretreated mCRPC. We prospectively assessed the effect of AR-V7 expression in basal CTCs on response to first-line enzalutamide in chemo-naive mCRPC patients (pts).

Methods

Phase II open-label study in chemo-naïve mCRPC pts ECOG 0-1. PCWG2 criteria are used for response evaluation. Pts received enzalutamide 160 mg/d until clinical and/or radiographic disease progression. Primary objective is to assess the predictive value of TMPRSS2-ERG and secondary endpoints included assessment of biomarkers of resistance in CTCs, including AR-V7. Here we report the first results on AR-V7. Selection and detection of CTCs were performed using AdnaTest PCa Select and Detect kits following manufacturer's instructions. Specific primers were used to detect AR-V7 by qPCR. The accuracy of the PCR product was confirmed by Sanger sequencing.

Results

98 pts were included between February 5th and November 23th 2015. Pts characteristics are: median age 77.8y; ECOG 0/1 in 55/45%, median basal PSA 20 ng/dl and metastastic sites were: bone (81%), LN (50%), lung (15%) and liver (3%). With a median follow-up of 8.2 months, confirmed PSA response >50%/ > 90% was 80.6%/39.8%. Radiologic response was: PR 12.5%, SD 77.1% and PD 10.4%. Basal CTCs were observed in 35.7% (N = 35). AR-V7 expression in CTCs was observed in 24.2% (N = 8). In the AR-V7 pts, PSA response >50% was present in 50% (4/8 pts), and >90 in 37.5% (3/8pts). Radiologic response was: PR 12.5% (1/8), SD 50% (4/8), PD 25 (2/8). One pt (1/8) was lost of follow-up. No association was observed between AR-V7 and primary resistance (p = 0,67).

Conclusions

Detection of AR-V7 in basal CTCs is not an absolute predictor for early resistance to enzalutamide in first-line chemo-naive mCPRC. Further follow-up is needed to assess the quality of the responses and its impact on other efficacy endpoints (PFS and OS). Additional biomarkers are needed to guide treatment selection in this scenario.

Clinical trial identification

EudraCT: 2014-003192-28 / NCT02288936

Legal entity responsible for the study

SOGUG (Spanish Oncology Genitourinary Group)

Funding

Astellas

Disclosure

E. Grande: Research grant: Astellas. Speaker: Astellas Advisory: Janssen.

A. González del Alba: Advisory Boards: Bayer, Sanofi, Pfizer, Novartis, BMS.

I. Duran: Compensated Advisory Board: Roche-Genentech, Jansen, Amgen, Astellas, Pierre Fabre and Novartis. Research Funding: Jansen, Sanofi.

All other authors have declared no conflicts of interest.