## Clinical Presentation This patient presents with: - **Metastatic bone disease** (osteoblastic lesions on bone scan) - **Markedly elevated PSA** (145 ng/mL) - **Biochemical failure** despite 8 months of androgen deprivation therapy (ADT) - **Castrate testosterone level** (2.2 ng/mL, indicating adequate hormonal suppression) ### Definition of Castration-Resistant Prostate Cancer (CRPC) **High-Yield:** CRPC is defined by **all three criteria**: 1. Serum testosterone <50 ng/dL (or <1.7 nmol/L) — **achieved in this patient** 2. **Rising PSA** on two consecutive measurements ≥1 week apart (despite ADT) — **present here** 3. **Absence of new metastases** on imaging (or new metastases only on bone scan, not soft tissue) — **consistent with this case** **Key Point:** This patient meets all criteria for **Castration-Resistant Prostate Cancer (CRPC)** — the most lethal phenotype of advanced prostate cancer. ### Pathophysiology of CRPC ```mermaid flowchart TD A[Hormone-Sensitive PCa on ADT]:::outcome --> B{Selective pressure}:::decision B -->|Androgen receptor mutations| C[AR hypersensitivity]:::action B -->|Intracrine androgen synthesis| D[Local DHT production]:::action B -->|Neuroendocrine differentiation| E[AR-independent growth]:::action C --> F[CRPC phenotype]:::urgent D --> F E --> F F --> G[Rising PSA despite castrate testosterone]:::outcome ``` **Clinical Pearl:** CRPC develops in ~30% of men treated with ADT for metastatic disease. The mechanism involves: - **AR mutations** → hypersensitivity to low androgen levels - **Intracrine synthesis** → local DHT production by tumour cells - **Neuroendocrine differentiation** → AR-independent growth - **Clonal selection** → emergence of aggressive, treatment-resistant clones ### Management of CRPC **High-Yield:** For metastatic CRPC (mCRPC), options include: | Agent | Mechanism | Indication | |---|---|---| | **Abiraterone acetate** | CYP17A1 inhibitor (blocks androgen synthesis) | First-line mCRPC | | **Enzalutamide** | AR antagonist (AR-independent action) | First-line mCRPC | | **Docetaxel** | Microtubule stabilizer (chemotherapy) | mCRPC, visceral metastases | | **Cabazitaxel** | Taxane (post-docetaxel) | Docetaxel-resistant mCRPC | | **Radium-223** | Alpha emitter (bone-targeting) | Symptomatic bone metastases | **Tip:** In this patient with **bone-predominant mCRPC**, **abiraterone acetate + prednisone** or **enzalutamide** would be appropriate next steps, as they have demonstrated OS benefit in the mCRPC setting. [cite:Harrison 21e Ch 97; Campbell-Walsh Urology 12e Ch 126]
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