Src and Vegf, targeted by D and S respectively, have been implicated in CRPC progression. Moreover the unmet need for predictive markers has become pressing. We conducted a study to determine if the addition of either agents could prolong time to progression (TTP) on AA and to test a prespecified molecular signature.
This is a phase II study of AA in bone mCRPC patients randomized upon progression to combination with D or S, comparing the two treatment strategy. Endpoints include PFS, safety, survival, assessment of aprespecified signaling signature in pts with benefit vs primary resistance to AA (progression ≤ 4 months). Pts had pretreatment bone biopsy. Tumor Markers included, Androgen Receptor-N terminal (AR-N), AR-C terminal (AR-C), CYP17, Ki67, GR, ERG, Ki67 (%), pSrc, vegf, DNA repair genes by IHC and steroids by LCMS.
Study (03/2011-02/2015) accrued 179 bone mCRPC pts and median follow up 27ms (9-57). Medians: Age, 68 ys (range 45-87), PS ECOG 1 (range 0-1) baseline PSA 20.6 (range 0.5-1655). 27 (16%) pts have visceral mets, 40 (22%) prior chemo. Diagnostic Gleason Score was ≥8 in 71%. Upon progression 128/179 pts were randomized: 64 to D (AD) and 64 to S (AS). Of these 61 crossed over and 30 are still on treatment. Fifty Five pts had primary resistance to AA. Thirteen pts discontinued due to adverse events (2 AA, 6AD and 5 AS) Median (CI 95%) TTP and Overall Survival (OS) for the cohort are 12.85 (11.08, 14.98 ) and 26.26 ( 23.21, 31.93 ) ms respectively. There is no difference for drug sequence. On multivariate analysis, primary resistance to AA (p
D or S do not improve AA efficacy or overcome primary resistance. Validation of prespecified androgen signaling signature predictive of AA response is planned in a multi-institutional study.
Clinical trial identification
Legal entity responsible for the study
MD Anderson Cancer Center
E. Efstathiou: research support, ad board honoraria; Janssen, Astellas, Sanofi, Medivation, Takeda.
C. Logothetis: Research: BMS, Medivation, Sanofi, Astellas, Janssen. Advisory boards: Astellas, AstraZeneca, Janssen, Sanofi, Bayer, Medivation, Clovis, Oncology, Churchill Pharmaceuticals.
All other authors have declared no conflicts of interest.