The CAPItello-281 trial shows the benefit of the AKT inhibitor capivasertib is on a spectrum. Patients with 100% PTEN protein loss by IHC derive a much greater benefit than those with partial loss, suggesting a quantitative biomarker may optimize patient selection.

Because PTEN loss is an early, truncal mutation in prostate cancer, clinicians should perform NGS testing on the first day a patient is seen. This proactive approach ensures that crucial biomarker information is not lost and is available to guide future treatment decisions, such as the use of an AKT inhibitor, should the disease progress.

The AKT pathway, activated by PTEN loss, drives cancer growth independently of the androgen receptor, which controls PSA production. This discordance means clinicians cannot rely on PSA alone and must use systematic imaging to detect progression in this specific patient subgroup.

Patients with high-risk genomic features like PTEN or TP53 loss may develop new or worsening metastatic disease visible on imaging without a rise in their PSA levels. This mandates routine cross-sectional imaging, as PSA alone is an unreliable marker for progression in this subgroup.

Data from the CAPItello trial showed a significant number of patients with PTEN deficiency experienced radiological progression without a corresponding PSA increase. This challenges the standard reliance on PSA for monitoring in high-risk prostate cancer and suggests a need for more frequent, personalized imaging protocols to detect progression earlier.

In patients with PTEN loss, cancer growth is driven by the PI3K-AKT pathway, which doesn't activate the PSA gene. This can lead to significant disease progression with a low or stable PSA, making PSA a poor surrogate for disease activity in this sub-population.

The CAPItello-281 trial showed that the clinical benefit of adding the AKT inhibitor capivasertib is directly proportional to the degree of PTEN loss. The greatest separation in survival curves was seen in patients with 99-100% PTEN loss by IHC, suggesting the current trial entry cutoff of >90% may be too broad for optimal patient selection.

Patients with PTEN-deficient prostate cancer often experience significant clinical or radiographic disease progression without a correspondingly rapid or high rise in PSA levels. This biological characteristic makes PSA an unreliable marker, necessitating a proactive strategy of frequent imaging to detect progression and intervene in a timely manner.

Unlike androgen receptor mutations that arise under treatment pressure, PTEN loss is an earlier event. Therefore, tissue from an original biopsy or prostatectomy remains informative for testing PTEN status when a patient relapses with metastatic disease, simplifying the diagnostic process and avoiding invasive re-biopsies.