Definition of Castrate-Resistant Prostate Cancer (CRPC)
Castrate-resistant prostate cancer is defined as disease progression—evidenced by a rising PSA level and/or radiographic progression—that occurs despite maintaining castrate levels of serum testosterone (less than 50 ng/dL or 1.7 nmol/L) through medical or surgical castration. 1
Biochemical Criteria for CRPC
The Prostate Cancer Clinical Trials Working Group 2 established specific PSA criteria that must be met: 1
- PSA must rise greater than 2 ng/mL above the nadir value
- The rise must be at least 25% over the nadir
- The rise must be confirmed by a second PSA measurement at least 3 weeks later
- Castrate testosterone levels (<50 ng/dL) must be documented concurrently
Radiographic Criteria for CRPC
Disease progression can also be defined radiographically using Response Evaluation Criteria in Solid Tumors (RECIST) adapted for prostate cancer, showing: 2
- New bone lesions on imaging (two or more new lesions on bone scan)
- Progression of soft tissue metastases
- Development of new metastatic sites
Critical Distinction: The Androgen Receptor Remains Active
Despite castrate levels of circulating androgens, the androgen receptor continues to drive disease progression in CRPC through multiple mechanisms. 1, 3, 4 This understanding is fundamental because:
- The tumor adapts by synthesizing its own intratumoral androgens 3, 5
- Androgen receptor overexpression occurs 4
- Mutant androgen receptors develop with promiscuous ligand recognition 4
- Upregulation of enzymes involved in androgen synthesis enables continued AR signaling 3, 5
Clinical Presentations of CRPC
CRPC manifests in distinct clinical states that guide treatment decisions: 1
Non-Metastatic CRPC (nmCRPC)
- Rising PSA with castrate testosterone
- No radiographic evidence of metastatic disease on conventional imaging
- Patient typically asymptomatic
Metastatic CRPC (mCRPC)
- Documented metastatic disease on imaging
- Can be asymptomatic/minimally symptomatic or symptomatic
- Performance status becomes critical for treatment selection
Timing and Natural History
Most patients with advanced prostate cancer initially respond to androgen deprivation therapy but progress to CRPC on average between 1-3 years after initiating castration. 1 This progression is inevitable, not a treatment failure, as the disease adapts to the low-androgen environment. 1
Modern Therapeutic Implications
The recognition that CRPC remains androgen receptor-driven despite castration has revolutionized treatment: 1, 6
- Next-generation AR-signaling inhibitors (enzalutamide, abiraterone) provide survival benefit 1, 3
- Chemotherapy with docetaxel and cabazitaxel improves survival 1, 7
- Novel agents like 177Lu-PSMA-617 offer additional options for PSMA-positive disease 8
- Continuation of ADT to maintain castrate testosterone remains essential throughout all treatment phases 8
Common Pitfall to Avoid
Never discontinue androgen deprivation therapy when CRPC develops. 8 The term "castration-resistant" does not mean androgen-independent—maintaining castrate testosterone levels remains critical even when adding additional therapies, as the disease continues to depend on AR signaling pathways. 3, 4