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.

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.

Intensive treatments like ADT plus an ARPI can suppress a patient's PSA so effectively that it becomes an unreliable marker of disease status. Patients may show radiographic progression on scans even while their PSA remains low and they feel clinically well. This discordance necessitates periodic imaging to avoid missing actual disease progression.

PTEN loss is seen very early in prostate cancer development. However, its primary role is not initiating the cancer but rather accelerating its progression in grade, stage, and disease state. The initial driver is more often related to androgen receptor biology.

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.

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.

While seen early, even in low-grade cancers, PTEN loss is primarily associated with the cancer's progression to more aggressive forms. It correlates with transitions to higher grades, more advanced stages, and ultimately, metastatic states, marking it as a critical event in the disease's natural history.