Background Hotspot activating mutations in AKT1 and PIK3CA occur uncommonly in mPC. The incidence and clinical course of patients (pts) with AKT1/PIK3CA hotspot mutations (A/P HSM) is poorly characterised. Methods We performed deep targeted sequencing on 1381 cell-free DNA samples from 773 pts with mPC. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), time to PSA progression (TTPP) on first-line metastatic CRPC therapy (1L mCRPCT) and overall survival (OS, defined as time from 1L mCRPCT to death). The control cohort consisted of 196 mCRPC pts with wild-type AKT1/PIK3CA treated with 1L abiraterone + prednisone (ABI) or enzalutamide (ENZ). Results Truncal A/P HSM were identified in 5.5% (31/567) of pts with detectable ctDNA, of which p.E17K (n=10) and p.E545K/Q/A (n=12) mutations were most common. When compared to the control cohort, tumors with A/P HSM had a significantly higher rate of TP53 defects (74% vs. 52%, P=0.03), fewer copies of AR (median 4.7 vs. 10.3, P=0.02), but similar PTEN alterations. 27 pts with A/P HSM had evaluable clinical data. At diagnosis, median age was 62.4 y, 66.7% had Gleason score ≥8, 53.8% presented with metastatic disease, and median PSA was 27 (range 6.3 – 9999). 11 pts (40.7%) had ADT plus either docetaxel or enzalutamide in castration-sensitive setting. Comparing the pts with A/P HSM to the control cohort, median time from ADT to CRPC was 11.5 m vs. 17.6 m (HR 1.18, 95% CI 0.78 – 1.79, P=0.46); median OS was 19.6 m vs. 27.3 m (HR 1.71, 95% CI 1.1 to 2.8, P=0.03). 23 pts had ABI or ENZ as 1L mCRPCT. PSA50 was 57% vs. 70% in the control cohort, P=0.19; median TTPP on 1L CRPCT was 5.8 m vs. 8.2 m (HR 1.18, 95% CI 0.7 – 2.0, P=0.54). A pt with an AKT1 p.E17K mutation received ipatasertib as third-line therapy for mCRPC. PSA50 was achieved (baseline PSA 520, nadir PSA 251 ug/L), and TTPP was 5.9 m. Conclusions Our data shows mPC pts with A/P HSM have significantly worse overall survival, and may have an attenuated response to androgen-axis targeted therapy than AKT1/PIK3CA wild-type pts. This subset of pts may benefit from AKT inhibitor therapy. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure S.Y.F. Fu: Travel / Accommodation / Expenses: Roche. S. Yip: Advisory / Consultancy: Bayer. B. Tran: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen-Cilag; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Tolmar; Advisory / Consultancy: Ipsen. F. Saad: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sanofi. K.N. Chi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: ESSA; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tokai Pharmaceuticals; Research grant / Funding (institution): Lily/ImClone; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.