What is the recommended treatment for a patient with rising Prostate-Specific Antigen (PSA) levels and a history of Crohn's disease, who previously received Abiraterone (abiraterone acetate) and Leuprolide (leuprolide acetate), and has stable prostatomegaly and no evidence of metastasis?

Management of Rising PSA After Discontinuation of Abiraterone and Lupron

Restart androgen deprivation therapy immediately with a GnRH analog (Lupron) and strongly consider adding enzalutamide 160 mg daily as combination therapy, given the rapid PSA kinetics (doubling time approximately 3-4 months), PSMA-PET evidence of active disease, and history of high-risk features. 1

Risk Stratification and Urgency of Treatment

Your patient demonstrates multiple high-risk features that mandate immediate systemic therapy rather than observation:

• PSA doubling time of approximately 3-4 months (PSA rose from 0.06 to 0.19 over 10 months), which is classified as high-risk and associated with rapid progression and prostate cancer-specific mortality 1
• PSMA-PET positive disease with moderate-to-mild radiotracer uptake in bilateral hemipelvis indicates active disease requiring systemic therapy 1
• Prior treatment with intensive therapy (abiraterone + Lupron) followed by biochemical recurrence suggests aggressive biology 1

The natural history for men with rising PSA after primary therapy is highly variable, but for those with rapid PSA kinetics like your patient, early therapy may be life-saving as this marks progression to lethal variants of the disease 2

Treatment Algorithm

Primary Recommendation: ADT + Enzalutamide Combination

Restart hormonal therapy with:

• GnRH analog (Lupron) at standard dosing to achieve castrate testosterone levels (<50 ng/dL) 1
• Enzalutamide 160 mg orally once daily as combination therapy 1

Rationale for this approach:

• Early hormonal therapy is indicated for short PSA doubling time (<12 months) after local treatments, and delaying ADT until symptomatic disease is inappropriate 1
• The combination of ADT plus enzalutamide is recommended as primary treatment for high-risk biochemical recurrence 1
• Sequential use of enzalutamide after abiraterone can provide benefit in selected patients, particularly those who demonstrate early PSA response 3

Alternative Consideration: ADT + Abiraterone Re-challenge

If enzalutamide is not available or contraindicated, restarting abiraterone acetate 1000 mg daily with prednisone 5 mg twice daily plus ADT is a reasonable alternative 2, 4

However, note that:

• Cross-resistance between abiraterone and enzalutamide exists, though sequential therapy can benefit a subset of patients 3
• Abiraterone with prednisone demonstrated survival benefit in metastatic CRPC in the COU-AA-301 trial (median survival 15.8 vs 11.2 months) 4
• In high-risk non-metastatic disease, abiraterone with ADT significantly improved metastasis-free survival (82% vs 69% at 6 years) 5, 6

Critical Considerations for Crohn's Disease

The presence of active Crohn's disease significantly impacts treatment selection:

• Avoid or minimize corticosteroid use (prednisone/prednisolone) given the patient's Crohn's disease, as corticosteroids carry high risk of serious adverse effects including infections, bone loss, glucose intolerance, and are ineffective for maintaining remission in Crohn's 7
• If abiraterone is chosen, the mandatory prednisone 5 mg twice daily poses increased risk in this patient 4
• Enzalutamide does not require concurrent corticosteroids, making it the preferred androgen receptor pathway inhibitor in this clinical context 1
• Monitor closely for Crohn's flares during systemic therapy, as stress from cancer treatment and medications can exacerbate inflammatory bowel disease 7

Monitoring Strategy

Implement intensive monitoring protocol:

• PSA every 3 months initially, with target of PSA <0.2 ng/mL within 6-12 months of treatment initiation 1
• Testosterone monitoring to confirm castrate levels (<50 ng/dL) achieved with ADT reinitiation 1
• Repeat PSMA-PET at 6 months to assess response of PSMA-avid lesions to systemic therapy 1
• Early PSA response assessment at 4 weeks: A PSA decline >50% at 4 weeks after enzalutamide initiation predicts long-term survival and identifies patients who benefit from this sequential therapy 3

Treatment Duration and Progression Criteria

Continue treatment until progression, defined as meeting two of three criteria:

• PSA progression 2
• Radiographic progression 2
• Clinical progression 2

Do not stop therapy based on PSA changes alone, as PSA may rise initially (flare) before declining, particularly with differentiating agents 2

Key Pitfalls to Avoid

• Do not delay treatment waiting for symptomatic disease in a patient with rapid PSA kinetics and PSMA-PET positive findings 1
• Do not use observation alone in this high-risk scenario, as this approach is reserved for patients with very slow PSA kinetics or limited life expectancy 8
• Avoid spironolactone if patient requires it for cardiac conditions while on abiraterone, as it may exert androgenic properties and compromise abiraterone effectiveness 9
• Confirm testosterone recovery before restarting ADT (testosterone should be ≥150 ng/dL and patient should not have received hormonal therapy for minimum 1 year) 10