What is the optimal management for a patient receiving androgen deprivation therapy who now has biochemical recurrence (rising PSA)?

Management of Biochemical Recurrence in Patients Already on ADT

For patients already receiving ADT who develop biochemical recurrence, the optimal strategy depends critically on risk stratification: switch to intermittent ADT if PSA doubling time remains >12 months, but intensify therapy with abiraterone plus prednisone (or enzalutamide) if high-risk features are present (PSA doubling time <12 months, Gleason ≥8, or node-positive disease). 1, 2

Initial Assessment and Risk Stratification

When a patient on ADT develops rising PSA, the first step is determining whether this represents true progression or requires treatment modification:

• Calculate PSA doubling time (PSADT): This is the single most important prognostic factor. PSADT >12 months indicates low risk of prostate cancer-specific mortality over 10 years, while PSADT <12 months signals aggressive disease requiring treatment intensification. 1, 3

• Obtain PSMA PET/CT imaging: This is now the standard restaging modality, far superior to conventional CT and bone scan, and can detect occult metastatic disease even at low PSA levels. 1, 3 Conventional imaging has extremely low yield when PSA <1.0 ng/mL. 3

• Review original pathology: High-grade disease (Gleason ≥8) and node-positive status at diagnosis identify patients who benefit from treatment intensification rather than observation. 1, 2

Treatment Algorithm Based on Risk Features

For Low-Risk Biochemical Recurrence (PSADT >12 months, no metastases on imaging):

Switch from continuous ADT to intermittent ADT (IADT). 1

• IADT demonstrates non-inferiority to continuous ADT for overall survival in multiple meta-analyses, with superior quality of life during off-treatment intervals. 1

• Qualifying criteria for IADT: High-risk biochemical recurrence is defined as PSADT <1 year after radical prostatectomy or interval to recurrence <18 months after radiation therapy, OR Gleason score 8-10. 1

• IADT protocol: Continue ADT until PSA becomes undetectable (<0.2 ng/mL), then suspend treatment. Reinitiate when PSA rises to ≥2.0 ng/mL (post-prostatectomy) or ≥5.0 ng/mL (post-radiation). 4

• Patients must be willing to adhere to frequent PSA monitoring every 3-4 months during off-treatment periods. 1, 3

For High-Risk Biochemical Recurrence (PSADT <12 months, Gleason ≥8, or node-positive):

Intensify systemic therapy by adding abiraterone 1000 mg daily plus prednisone 5 mg twice daily to ongoing ADT, continuing indefinitely until progression. 2

• The STAMPEDE trial demonstrated a 79% relative improvement in failure-free survival (HR 0.21,95% CI 0.15-0.31) when abiraterone was added to ADT in node-positive non-metastatic disease. 2

• Alternative option: Enzalutamide 160 mg daily can be used instead of abiraterone, particularly if hepatotoxicity concerns exist. The EMBARK trial showed metastasis-free survival benefit with enzalutamide plus ADT. 4

• Continue treatment indefinitely in patients achieving complete response, not for a preset duration. Therapy should only be stopped at progression. 2

Critical Monitoring Requirements

• PSA every 3-6 months to detect progression early. 2

• PSMA PET/CT every 6-12 months to verify ongoing complete response and detect oligoprogressive disease amenable to salvage radiation. 2

• Liver function tests regularly when using abiraterone, as grade 3-5 hepatotoxicity occurs in ~7% of patients. 2

• Blood pressure and potassium monitoring for abiraterone-related hypertension (21% incidence) and hypokalemia (12% incidence). 2

Common Pitfalls to Avoid

• Do not reflexively continue continuous ADT without risk stratification. Patients with PSADT >12 months should transition to intermittent therapy to preserve quality of life. 1, 3

• Do not order conventional bone scans or CT at low PSA levels (<1.0 ng/mL) – the yield is <5% and PSMA PET is vastly superior. 1, 3

• Do not delay treatment intensification in high-risk patients. Early addition of abiraterone or enzalutamide in node-positive or high-grade disease improves outcomes. 2

• Avoid starting ADT based solely on PSA rise if PSADT >12 months and no metastases are present – active surveillance with close monitoring is appropriate in this scenario. 1, 3

Salvage Options if Progression Occurs

• For oligoprogressive disease on PSMA PET: Consider salvage pelvic radiotherapy combined with continued systemic therapy. 2

• For widespread progression on abiraterone: Switch to enzalutamide, or add docetaxel chemotherapy (75 mg/m² every 3 weeks for 6 cycles) to ADT. 2, 5

• For castration-resistant progression: Transition to CRPC-specific therapies per established guidelines. 1