Background: ABI+P and ENZ have similar efficacy for 1st-line treatment of mCRPC but cross-resistance confounds treatment with the alternate agent at progression. The optimal sequencing has not been prospectively investigated and predictive biomarkers are needed. Methods: A multi-centre trial of ABI+P followed by ENZ at PSA progression (arm A) vs ENZ followed by ABI+P (arm B). Primary endpoints were PSA decline > 50% (PSA50) on 2^nd-line therapy and time to 2^nd PSA progression (TT2P) (from start of 1^st-line). Deep-targeted sequencing of serial samples of circulating tumour DNA (ctDNA) was performed. Results: 202 pts (101/ arm) were accrued with median follow-up 22.3 months (m). 65 pts from arm A and 71 from arm B crossed-over to 2nd-line treatment and 30 pts (15/arm) stopped treatment without cross-over. Baseline characteristics at time of 2nd-line therapy were balanced: median age 75 (range 50-93), PSA 14.5 (6.6-62.1), alkaline phosphatase > upper limit of normal (ULN) in 39% of pts and bone/liver metastasis (mets) in 89%/9%. ECOG PS was 0-1 in 89% vs 76% of pts for arm A vs arm B (p = 0.044) and LDH was > ULN in 25% vs 8% (p = 0.013). PSA50 for 2^nd-line therapy for arm A vs arm B was 34% vs 4% (p˂0.001) and median time to PSA progression on 2^nd-line therapy (TTPP) was 2.7 m vs 1.3 m (HR 0.38, 95% CI 0.26-0.56). For the intention-to-treat population, TT2P was 13.6 vs 11.9 m (HR 0.75, 95% CI 0.53-1.06). Median overall survival (OS) was not reached vs 24.3 m (HR 0.82, 95% CI 0.53-1.27). On multivariable analysis, factors associated with 2^nd-line TTPP were: bone mets (HR 2.22, 95% CI 1.08-4.54), liver mets (HR 3.18, 95% CI 1.21-8.41) and treatment arm A vs B (HR 0.27, 95% CI 0.17-0.40). At progression, AR gene copy number increased in 14% of evaluable pts (7/49) and AR L702H/T878A(S) mutations were present in 8% of pts. ctDNA fraction ≥2% at baseline was associated with worse TT2P (HR 2.04, 95% CI 1.43 - 2.90) and OS (HR 4.07, 95% CI 2.40-6.91). Conclusions: The sequence of ABI+P followed by ENZ was associated with superior PSA50 and TTPP on 2^nd-line therapy. AR alterations associated with ABI+P and ENZ resistance were detectable in ctDNA. Clinical trial information: NCT02125357