What is the recommended treatment approach for an 85-year-old male with castration-resistant prostate cancer (CRPC), a Prostate-Specific Antigen (PSA) level of 10, and Prostate-Specific Membrane Antigen (PSMA) prostate enhancement with no metastatic sites?

Treatment Approach for Non-Metastatic CRPC with PSMA-Positive Prostate

For this 85-year-old man with castration-resistant prostate cancer confined to the prostate without metastases, the priority is continuing androgen deprivation therapy indefinitely, with strong consideration for adding enzalutamide or apalutamide if PSA doubling time is ≤10 months, as these agents significantly improve metastasis-free survival and overall survival in non-metastatic CRPC. 1, 2, 3

Critical First Step: Confirm Non-Metastatic Status and Calculate PSA Doubling Time

• Verify castrate testosterone levels (<50 ng/dL) to confirm true castration resistance, as this is a prerequisite for any CRPC diagnosis 1, 2
• Calculate PSA doubling time (PSADT) from serial PSA measurements, as PSADT ≤10 months defines high-risk non-metastatic CRPC that warrants intensified therapy 1, 2
• Confirm absence of metastases on conventional imaging (CT and bone scan), recognizing that PSMA PET may detect disease not visible on conventional imaging but treatment decisions should be based on conventional imaging per current guidelines 1

Androgen Deprivation Therapy: The Foundation

Continue androgen deprivation therapy (ADT) indefinitely regardless of any additional treatments initiated, as discontinuation leads to disease progression even with novel agents 1, 3

Treatment Selection Based on PSA Doubling Time

If PSADT ≤10 Months (High-Risk nmCRPC):

Add enzalutamide 160 mg daily OR apalutamide 240 mg daily to ongoing ADT, as both agents demonstrate:

• Metastasis-free survival improvement of approximately 24 months (40.5 months vs 16.2 months for apalutamide; similar for enzalutamide) 1, 2
• Overall survival benefit (HR 0.73 for enzalutamide, HR 0.78 for apalutamide) 2
• Category 1, strong recommendation from multiple guideline societies 1, 2

Enzalutamide may be preferred in this 85-year-old patient due to:

• Lower risk of falls compared to apalutamide (9.3% vs 15.6% with placebo) 1
• No requirement for concurrent steroid administration 4
• FDA-approved for CRPC with demonstrated survival benefit 3

Key monitoring requirements:

• Blood pressure monitoring for hypertension risk 2, 3
• Mental status assessment for cognitive impairment risk 1, 2
• Seizure precautions (0.6% risk, though higher in patients with predisposing factors) 3
• Serial PSA every 3-6 months and conventional imaging every 6-12 months 2

If PSADT >10 Months (Lower-Risk nmCRPC):

Continue ADT alone with close monitoring, as the benefit-to-harm ratio of adding AR inhibitors is less favorable in this population 1, 2

Important Caveats for This 85-Year-Old Patient

Age and performance status considerations:

• At 85 years, carefully assess functional status, comorbidities, and life expectancy before intensifying therapy 1
• If performance status is poor (ECOG ≥2), the toxicity risks of AR inhibitors may outweigh benefits 5
• Cardiovascular comorbidities are particularly relevant, as enzalutamide carries increased risk of major adverse cardiovascular events 2

The PSMA-positive finding on imaging:

• While PSMA positivity confirms prostate cancer activity, treatment decisions for non-metastatic CRPC should be based on conventional imaging (CT/bone scan), not PSMA PET 1
• PSMA PET may detect micrometastatic disease not visible on conventional imaging, but current guideline recommendations are based on conventional imaging definitions 6
• If PSMA PET shows metastatic disease not seen on conventional imaging, this represents a gray zone where clinical judgment is required, but the patient would technically still qualify for nmCRPC treatment approaches 6

What NOT to Do

Avoid these approaches in non-metastatic CRPC:

• Do not use chemotherapy (docetaxel, cabazitaxel) in the non-metastatic setting, as these are reserved for metastatic disease 1, 5
• Do not use radium-223, as it is only indicated for symptomatic bone metastases 1, 5
• Do not use abiraterone in nmCRPC, as it lacks FDA approval and guideline support in this setting (unlike enzalutamide and apalutamide) 1, 2
• Do not discontinue ADT when adding AR inhibitors 1, 3

Treatment Suspension Option

For patients achieving PSA <0.2 ng/mL after 36 weeks of enzalutamide plus ADT, treatment can be suspended and reinitiated when PSA rises to ≥2.0 ng/mL (post-prostatectomy) or ≥5.0 ng/mL (post-radiation), though this applies to nmCSPC with biochemical recurrence rather than CRPC 3

Monitoring for Disease Progression

Progression to metastatic CRPC requires treatment modification:

• If metastases develop despite AR inhibitor therapy, options include switching to alternative AR inhibitor, adding docetaxel, or considering clinical trials 5, 4
• Median time to metastasis with AR inhibitors is approximately 40 months, providing substantial disease control 1, 2