Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or > 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m² IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368.