2275 - Activating mutations in AKT1/PIK3CA are associated with poor clinical outcomes in metastatic prostate cancer (mPC)

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.

Clinical trial identification

Editorial acknowledgement

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.