Background and objective Sequential tissue biopsies taken during clinical trials of novel systemic anticancer therapies for advanced prostate cancer (PCa) may aid pharmacodynamic evaluation and biomarker discovery. We conducted a single institution phase-II open-labeled randomized study to assess the safety, tolerability, and early efficacy of docetaxel chemotherapy plus androgen deprivation therapy (ADT) vs. ADT alone for patients with advanced non–castration-resistant PCa with sequential prostatic biopsies. Patients and methods We randomized 30 patients with newly diagnosed high-grade locally advanced or metastatic (cT3–4/N0–1/M0–1) PCa to receive ADT with ( n = 15) or without ( n = 15) docetaxel. Transrectal ultrasound–guided prostatic biopsies were taken at randomization and ~22 weeks after treatment initiation. Primary end point: biochemical response rate. Secondary end points: time to progression and tumor profiling. Results Both treatments appear to be well tolerated, and there was no difference in mean nadir prostate-specific antigen and time to prostate-specific antigen relapse between treatment arms ( P >0.05). No adverse effects of pre- and post-treatment prostatic biopsies were observed. The study was neither designed nor sufficiently powered to demonstrate statistically significant differences in oncological outcomes or safety profiles between the 2 treatment arms. Conclusions Despite the lack of statistical power, our study suggests that docetaxel and ADT in combination may be well tolerated with apparently similar short-term efficacy compared with ADT alone for high-grade locally advanced or metastatic non–castration-resistant PCa, Sequential prostatic biopsies may provide tissue for tumor profiling to yield mechanistic or prognostic insights relating to novel systemic anticancer therapies. [ABSTRACT FROM AUTHOR]