AKT inhibition by Ipatasertib in mCRPC: The A.MARTIN Randomized Phase II trial

Circulating tumor DNA (ctDNA) dynamics associate with treatment response and radiological progression-free survival (rPFS): Analyses from a randomized phase II trial in metastatic castration-resistant prostate cancer (mCRPC).

Abstract Number : 5508

Abstract Type : Oral Abstract Session

Indication : Metastatic Castration Resistant Prostate Cancer

Intervention : Ipatasertib with or without abiraterone

Company : Roche

Technology : Small Molecule


Baseline (BL) ctDNA positivity correlated with radiological progression-free survival (rPFS; HR: 1.8 [95% CI 1.3-2.6], p , 0.01); this association with rPFS was maintained in a multivariate cox model with . 5 baseline clinical variables (HR: 1.6 [95% CI 1.1-2.4]; p = 0.011). Patients with a C3D1 reduction in ctDNA had superior rPFS compared to patients with a C3D1 increase in ctDNA (HR: 2 [95% CI 1.3-3.2], p , 0.01). The rate of ctDNA clearance at C3D1 was higher in the Ipatasertib 400mg arm compared to placebo (56.3% versus 24.4%, p , 0.01). We find that changes in ctDNA associated with best confirmed overall response (p = 0.024); CR patients had the greatest reduction in ctDNA (mean of -23.4%), followed by PR (-16.3%), then SD (-4.1%), and lastly PD patients (-1.3%). Changes in ctDNA levels correlated with SLD changes (rs = 0.289, p = 0.05), and also PSA changes (rs = 0.33, p , 0.01). Changes in ctDNA were associated with rPFS in a multivariate cox analysis that included PSA change (p , 0.01), as well as in a separate multivariate analysis that included SLD change (p , 0.01). Lastly, we explored CNVs and observed emerging resistance mutations in progression samples, including alterations in TP53, AR, FOXA, PTEN, and PI3K/AKT pathway genes


ctDNA analyses may help (i) identify poorer prognosis disease at baseline, (ii) inform on treatment response (CR/PR/SD/PD) and radiological progression free survival (rPFS) in on-treatment (C3D1) samples, and (iii) can elucidate emerging resistance mechanisms at disease progression.


Combined ipatasertib and abiraterone improved rPFS in patients with mCRPC with PTEN loss. ctDNA analysis might help in better treatment response and disease progression.

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