What are the treatment options for biochemical recurrence vs castrate-resistant recurrence of prostate cancer?

Treatment Options for Biochemical Recurrence vs Castrate-Resistant Recurrence of Prostate Cancer

Biochemical Recurrence (Non-Metastatic)

For patients with biochemical recurrence after radical prostatectomy without metastatic disease, salvage radiation therapy to the prostate bed is the primary curative-intent treatment, with androgen deprivation therapy (ADT) added for those with high-risk features. 1

Risk Stratification and Treatment Selection

• High-risk BCR features include PSA ≥0.7 ng/mL, Gleason Grade Group 4-5, PSA doubling time (PSADT) ≤6 months, persistently detectable post-operative PSA, or seminal vesicle involvement 1

• Low-risk BCR features include PSADT >12 months, Gleason score <8, longer time to recurrence (>3 years post-surgery), and pathological stage ≤pT3a N0 1

Treatment Algorithm for BCR After Radical Prostatectomy

High-Risk BCR (PSADT ≤9 months):

• Salvage radiation therapy (minimum 64-66 Gy to prostate bed) PLUS ADT is recommended, with optimal outcomes when PSA is <0.5 ng/mL at treatment initiation 1
• Enzalutamide plus leuprolide combination is now FDA-approved for high-risk BCR (PSADT ≤9 months), providing significant metastasis-free survival benefit over ADT alone 2, 3
• Initiate salvage radiation early—outcomes deteriorate significantly when PSA rises above 1.5 ng/mL (6-year progression-free survival drops from 48% to 18%) 1

Low-Risk BCR (PSADT >12 months):

• Active surveillance is appropriate without immediate systemic therapy 1
• Avoid early continuous ADT, as this may induce castration resistance before metastases develop (non-metastatic castration-resistant prostate cancer) 3
• Monitor PSA every 3-4 months and reassess risk stratification 1

Imaging Considerations

• PSMA PET imaging should be used to exclude low-volume metastatic disease before initiating salvage local therapy, as it detects disease at PSA levels <2.0 ng/mL where conventional imaging (CT, bone scan) is typically negative 1
• Conventional imaging rarely detects metastases when PSA <5 ng/mL 1

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Castrate-Resistant Recurrence

For castration-resistant prostate cancer (CRPC), treatment depends critically on metastatic status (M0 vs M1), with systemic therapy intensification being the cornerstone of management.

Defining CRPC

• Disease progression despite ADT with castrate testosterone levels (<50 ng/dL) 1
• Progression manifests as continuous PSA rise (minimum 2.0 ng/mL with values at 1-week intervals), radiographic progression, or clinical symptoms 1
• Confirm castrate testosterone levels before diagnosing CRPC 1

Treatment Algorithm for CRPC

Non-Metastatic CRPC (M0):

• Clinical trial enrollment is preferred 1
• Observation is acceptable for asymptomatic patients 1
• Secondary hormonal therapy options include antiandrogens (if not previously used), ketoconazole with glucocorticoids, or estrogens/progesterone, though none have proven survival benefit in randomized trials 1
• If prior combined androgen blockade was used, discontinue antiandrogen to assess for withdrawal response 1

Metastatic CRPC (M1):

• Docetaxel-based chemotherapy (every 3 weeks) plus corticosteroids is the preferred first-line systemic treatment, with proven survival benefit 1
• Bisphosphonates should be added for bone metastases 1
• Secondary hormonal therapy remains an option (antiandrogens, ketoconazole, estrogens) 1
• Systemic radiotherapy (samarium-153 or strontium-89) for widely metastatic painful skeletal involvement not responding to chemotherapy or external beam radiation 1
• 177Lu-PSMA-617 therapy is indicated after progression on at least one androgen receptor pathway inhibitor AND one taxane regimen, with confirmed PSMA-positive disease on PET imaging 4

Key Management Principles for CRPC

• PSA rise alone does not define treatment failure—continue effective chemotherapy if clinical progression is absent 1
• External beam radiation remains essential for symptomatic bone metastases, focal pain, or impending pathologic fractures 1
• Mitoxantrone with prednisone provides palliative benefit for painful bony metastases, though survival impact as second-line therapy post-docetaxel is unproven 1
• Consider neuroendocrine differentiation in patients not responding to ADT, especially with initial Gleason 9-10; biopsy accessible lesions and treat with cisplatin/etoposide or carboplatin/etoposide 1

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Critical Pitfalls to Avoid

• Do not use continuous ADT for low-risk BCR—this accelerates development of castration resistance without metastases 3
• Do not delay salvage radiation when indicated—efficacy drops dramatically as PSA rises above 0.5 ng/mL 1
• Do not add estramustine to docetaxel—increases toxicity without improving efficacy 1
• Do not rely on conventional imaging for BCR with PSA <5 ng/mL—use PSMA PET instead 1
• Always verify castrate testosterone levels before diagnosing CRPC to avoid misclassification 1