Background: Docetaxel is the standard 1st-line chemotherapy for mCRPC, while cabazitaxel prolongs survival after docetaxel progression. The activity of cabazitaxel in the 1st-line setting is unknown, while the molecular mechanisms of taxane sensitivity/resistance have been understudied. Clinically, a ≥30% PSA decline within 3 months predicts survival in docetaxel- and cabazitaxel-treated men. Molecularly, emerging evidence suggests that sensitivity/resistance to taxanes relates to the ability of microtubules to traffic AR into the nucleus. Circulating tumor cells (CTCs) represent a real-time biomarker to assess drug-target engagement (DTE) which may be predictive of clinical outcome, and novel enrichment techniques present opportunities for molecular testing. Methods: This is a multicenter phase 2 trial for chemo-naïve mCRPC. 100 men will be randomized (2:1) to 1st-line docetaxel or cabazitaxel. Following 4 cycles, if a ≥30% PSA decline is not achieved, men will switch to the alternative taxane; others will remain on the initial taxane until progression (PCWG2) or unacceptable toxicity. CTCs will be obtained at screening, baseline, after 1 and 4 cycles of chemotherapy, at crossover and at progression to interrogate mechanisms of taxane sensitivity/resistance. CTCs will be enriched via a prostate-specific microfluidic device, enumerated, and analyzed via multiplex confocal microscopy for microtubule bundling and AR localization. TaqMan PCR (and RNA sequencing) will be used to detect AR variants, as preliminary data show that variant ARv567 predicts taxane sensitivity while ARv7 predicts resistance. The primary clinical endpoint of the trial is achievement of a ≥50% PSA reduction during the treatment continuum. The primary molecular endpoint is analysis of DTE in CTCs, and correlation with PSA responses. The study will have 80% power to detect a 25% increase in PSA response rate with tight interclass kappa coefficients for primary biomarkers. Secondary endpoints include radiographic and PSA progression-free survival, objective response rates, overall survival, and safety. Clinical trial information: NCT01718353.