The advent of highly sensitive PSMA PET imaging is changing the management of biochemically recurrent prostate cancer. Rather than relying on fixed PSA thresholds from older trials like EMBARK to restart therapy, clinicians now use PET imaging at lower PSA levels to guide decisions, aiming to extend treatment-free intervals.
Despite showing a metastasis-free survival benefit in the EMBARC trial, enzalutamide monotherapy is being used less. The significant risk of gynecomastia, persistent fatigue, and most importantly, the lack of an overall survival advantage compared to ADT, have made it a less attractive option for patients and clinicians.
In a patient with high-risk features and a rapidly rising PSA, a negative PSMA PET scan should not be the final word. It may indicate the presence of PSMA-negative disease, a possibility that must be investigated with conventional cross-sectional imaging (CT scans) to ensure no tumors are being missed.
For patients showing a rising PSA shortly after stopping long-term Androgen Deprivation Therapy (ADT), it is crucial to check testosterone levels. They may still be castrated from the prior therapy, meaning their rising PSA actually signifies castration-resistant disease, which requires a completely different treatment approach.
A large meta-analysis (StopCap) revealed that while abiraterone improves prostate cancer-specific survival, it does not improve overall survival in men older than 75. This is likely due to increased cardiovascular toxicity, suggesting other ARPIs with cleaner safety profiles are a better choice for this elderly population.
The clinical distinction between de novo (presenting with metastases at diagnosis) and recurrent metastatic disease is more critical than traditional 'low vs. high volume' definitions. De novo disease is inherently more aggressive, providing a strong rationale for using intensive triplet systemic therapy even in patients who are technically classified as 'low volume'.
Contrary to what might be assumed, compelling preliminary data suggests that patients with BRCA2 mutations may be more resistant, not more sensitive, to radioligand therapies like lutetium-PSMA. This makes PARP inhibitors the clear first-line choice in this genetically-defined subgroup of patients with metastatic castration-resistant prostate cancer.
For patients who achieve a deep response to a PARP inhibitor but struggle with persistent hematologic toxicity despite dose reductions, a practical clinical strategy is to switch to a different agent within the same class (e.g., from olaparib to rucaparib). This may offer a chance for improved tolerability while maintaining therapeutic benefit.
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.
For high-risk, PTEN-deficient metastatic prostate cancer, a proposed strategy to maximize benefit while minimizing toxicity is sequential intensification. Clinicians can administer a triplet of ADT, an ARPI, and docetaxel first, and only after the chemotherapy course is complete, add the AKT inhibitor capivasertib to avoid severe, overlapping toxicities.
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.
Data from a head-to-head trial comparing lutetium-PSMA and docetaxel suggests a potential overall survival advantage for the sequence starting with chemotherapy. While PFS was similar, patients who received docetaxel first and then crossed over to lutetium at progression appeared to fare better, likely because they were guaranteed two life-prolonging therapies.