The clinical definition of "non-metastatic" prostate cancer is based on conventional imaging like CT and bone scans. However, with advanced PET scanning, it's clear these cases are biologically micro-metastatic. This discrepancy is crucial as clinical trial data for this stage is based on the older, less sensitive imaging standards.
For high-risk biochemically recurrent prostate cancer, intermittent androgen deprivation therapy (ADT) is the standard of care, not continuous therapy. This approach significantly improves quality of life, bone health, and metabolic health while effectively delaying progression to metastatic disease for years. Continuous therapy is vehemently discouraged in this setting.
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 CAPITELLO-281 trial found that while adding capivasertib to hormonal therapy was positive overall for PTEN-deficient prostate cancer, the benefit was most significant in patients with the most profound PTEN loss. This suggests that a simple positive/negative test may be insufficient, and quantitative IHC scoring could be necessary to select patients.
When using intermittent androgen deprivation, GnRH antagonists like relugolix are preferred over LHRH agonists like leuprolide. Antagonists allow for a much faster recovery of testosterone during off-treatment periods, which is a significant quality-of-life benefit for patients. With agonists, testosterone recovery can sometimes take years.
For patients with biochemically recurrent prostate cancer, the decision to treat hinges on PSA doubling time. A doubling time of over two years carries a low risk of metastasis, often warranting observation. Conversely, a doubling time under three months indicates a high risk of metastasis within three years, necessitating intervention.
In prostate cancer, the benefit of PARP inhibitors is overwhelmingly driven by BRCA2 mutations, which are more common than BRCA1. While PALB2 also shows a strong response, genes like BRCA1 offer only modest benefit, and ATM mutations show almost no response. This highlights the need for a gene-specific, not class-specific, approach to treatment.
A novel strategy for BRCA2-mutant metastatic prostate cancer is to use PARP inhibitors as an induction therapy for 6-10 months rather than continuously. This approach aims to achieve a deep response while preserving bone marrow, which is critical for tolerating future therapies like radioligands and chemotherapy in older patients with a long disease course.
In metastatic hormone-sensitive prostate cancer, patient outcomes vary dramatically. Triplet therapy is the default only for the highest-risk group: patients with de novo, high-volume disease, whose median survival on ADT alone is just three years. For all other patients, including those with low-volume or metachronous disease, doublet therapy is the standard.