The PRESTO trial evaluated adding apalutamide (APA) and abiraterone (Abby) to a standard LHRH analog. The triplet combination arm demonstrated increased toxicity without any additional efficacy gains compared to the doublet arm (LHRH + APA). This finding reinforces that more intensive combination therapy is not always better and can be detrimental in this setting.

Despite alpelisib directly targeting the upstream PIK3CA mutation, clinicians have almost completely shifted to the downstream AKT inhibitor capivasertib in the second-line setting. This practical decision is driven by capivasertib's significantly better side effect profile and ease of management.

The ERA SAFE study found that a bi-weekly, lower-dose docetaxel regimen for triplet therapy significantly lowers grade 3-4 adverse events compared to the standard 3-week schedule. It reduced the risk of neutropenic fever from 5.5% to 1.7% while maintaining similar efficacy, offering a safer alternative for frail or vulnerable patients.

The innovative Triple Switch trial treats all patients with a doublet therapy and then uses their PSA response at six months to guide further treatment. Patients whose PSA fails to reach a nadir are then randomized to receive docetaxel chemotherapy, testing a strategy of early intensification based on a real-time biological response rather than upfront risk stratification.

Using capivasertib in the hormone-sensitive setting is preferred because the cancer is more likely dependent on the AKT pathway for growth. In later, castration-resistant stages, additional genetic alterations can emerge, creating redundant growth signals and potentially diminishing the inhibitor's efficacy.

The panel suggests AKT inhibitor trials in prostate cancer have been disappointing due to suboptimal biomarker selection (e.g., PTEN IHC). A similar drug in breast cancer showed significant survival benefit when using a more precise NGS-based strategy, indicating a potential path forward if the right patient population is identified genetically.

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.

The standard of care for metastatic castration-sensitive prostate cancer has evolved. ADT plus an ARPI is now the baseline treatment for nearly every patient. Referring to it as 'intensification' is outdated and misrepresents its role as the new standard.

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.