What is the next best step in management for a patient with prostate cancer, rising PSA levels, and recent PSMA PET and CT CAP results, with a history of radiation therapy and treatments with Lupron (leuprolide) and Abiraterone (abiraterone acetate), and stable Crohn's disease?

Management of Rising PSA and Positive PSMA PET in a Patient with Prostate Cancer Post-Radiation Therapy

For a patient with prostate cancer showing rising PSA levels and positive PSMA PET findings after radiation therapy and prior hormonal treatments, initiation of a novel hormonal agent such as enzalutamide is the most appropriate next step in management.

Clinical Situation Assessment

• Patient has a history of prostate cancer treated with radiation therapy and was previously on Lupron (leuprolide) for 2 years 1
• Abiraterone was discontinued due to adverse effects 1
• PSA trend shows progressive rise:
  • PSA <0.04 (02/12/24,5/13/24,8/13/24)
  • PSA 0.06 (11/20/24)
  • PSA 0.13 (5/27/2024)
  • PSA 0.19 (9/22/25) 1
• PSMA PET from 9/26/25 showed:
  • Ill-defined nodular density with moderate radiotracer uptake in the anterior and inferior aspect of the right hemipelvis
  • Ill-defined density with mild uptake in the lateral and inferior aspect of the left hemipelvis 1
• CT CAP from 9/26/25 showed no evidence of metastatic disease, stable prostatomegaly, and stable Crohn's disease 1

Interpretation and Management Plan

1. Disease Status Classification

• The rising PSA pattern with positive PSMA PET findings but negative conventional imaging indicates biochemical recurrence progressing to early castration-resistant prostate cancer (CRPC) 1
• The patient has non-metastatic CRPC by conventional imaging but with PSMA-avid disease 1

2. Recommended Next Step

The patient should be started on enzalutamide as the next line of therapy. 1, 2

Rationale:

• Patient has previously failed on abiraterone (discontinued due to adverse effects) 1
• Enzalutamide is FDA-approved for castration-resistant prostate cancer and has shown efficacy in delaying metastasis in patients with rising PSA 2
• NCCN guidelines recommend sequential use of novel hormonal agents in patients who remain candidates for further systemic therapy 1

3. Monitoring Recommendations

• PSA measurements should be performed every 3-4 weeks initially to assess response 1
• Regular imaging follow-up with CT scans every 2-4 months 1
• Bone scintigraphy every 2-4 months 1
• Consider repeat PSMA PET in 3-6 months to assess response 1

4. Alternative Options (if enzalutamide is not tolerated)

• Apalutamide could be considered as an alternative novel hormonal agent 1, 3
  • Has shown similar efficacy to enzalutamide in non-metastatic CRPC 4
  • May provide deeper PSA responses compared to enzalutamide in some studies 5
• Darolutamide is another option with potentially fewer central nervous system side effects 1

5. Future Considerations

• If disease progresses on enzalutamide, consider:
  • Docetaxel chemotherapy if not previously used 1
  • 177Lu-PSMA-617 therapy (given positive PSMA PET findings) if disease progresses after docetaxel 1
  • Cabazitaxel as a later-line option 1

Important Clinical Considerations

• Enzalutamide dosage is 160 mg orally once daily, with dose reductions to 120 mg or 80 mg if adverse effects occur 2
• Monitor for potential adverse effects of enzalutamide:
  • Seizures (rare but serious concern, 0.6% incidence) 2
  • Fatigue, hypertension, and hot flashes are common side effects 1
• Continue androgen deprivation therapy (ADT) concurrently with enzalutamide 1, 2
• The patient's Crohn's disease should be monitored during treatment as it may affect medication tolerance 1

Treatment Decision Pitfalls to Avoid

• Do not rely solely on PSA for monitoring response; radiographic progression can occur without PSA elevation in up to 24.5% of patients on novel hormonal agents 1
• Avoid discontinuing therapy based on PSA progression alone; NCCN recommends continuing until clinical progression or intolerability 1
• Consider the patient's prior adverse effects with abiraterone when selecting the next agent and monitoring for side effects 1
• Do not delay treatment initiation as early intervention with novel hormonal agents has shown improved outcomes in delaying metastasis and improving survival 1