The efficacy of the AKT inhibitor Capivasertib is not uniform across all PTEN-deficient tumors. An analysis revealed that patients with 100% loss of the PTEN protein experienced the most significant benefit, with a 12-month improvement in radiographic progression-free survival. This highlights a direct correlation between the degree of protein loss and treatment response.

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.

While ctDNA is a powerful tool, it is not interchangeable with tissue testing for PI3K pathway alterations. Analysis from Capitello-291 showed PTEN deletions were the most discordant, with 11% of pathway alterations found only in tissue. This highlights the need for a complementary strategy, using both methods to ensure all eligible patients are identified for targeted therapy.

The approval of the AKT inhibitor Capivasertib has transformed PTEN testing from a prognostic tool for aggressive disease into a mandatory predictive test. Every patient with newly diagnosed metastatic prostate cancer should be assessed to determine eligibility for this targeted therapy, marking a significant shift in the standard of care.

For certain therapies like Enhertu, eligibility is based on immunohistochemistry (IHC), not NGS. Labs must run HER2 IHC in parallel because NGS, as a population-based test, can miss intratumoral heterogeneity (small clusters of positive cells) that IHC can detect, thus identifying more eligible patients for targeted therapy.

While Next-Gen Sequencing (NGS) provides genetic data, IHC directly measures the protein, is faster, cheaper, and requires less tissue. This makes it more scalable for routine clinical use, especially with small biopsy samples. High-level IHC loss correlates well with genetic loss seen on NGS.

Exploratory analysis shows that while patients with 100% PTEN loss have a much worse natural history than those with 90% loss, the therapeutic effect of capivasertib is stable across this spectrum. The drug effectively targets the pathway regardless of the magnitude of loss, making it a robust option for this entire subgroup.

While Next-Gen Sequencing (NGS) can detect PTEN genetic loss, Immunohistochemistry (IHC) is often more practical for routine clinical use. IHC directly measures protein loss, requires less tissue, is faster, more affordable, and highly scalable.

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.