Definition of Castration-Resistant Prostate Cancer
Castration-resistant prostate cancer (CRPC) is defined as disease progression—either biochemical (PSA rise), radiographic, or clinical—that occurs despite maintaining castrate serum testosterone levels below 50 ng/dL (or <1.7 nmol/L). 1, 2, 3
Core Diagnostic Criteria
CRPC diagnosis requires all three of the following components to be present simultaneously:
1. Castrate Testosterone Level
- Serum testosterone must be <50 ng/dL (<1.7 nmol/L), confirmed by laboratory testing 1, 3
- This threshold must be maintained throughout the disease course, not just at a single time point 3
- The patient must be on continuous androgen deprivation therapy (ADT) via LHRH agonist/antagonist or surgical castration 2, 4
2. Evidence of Disease Progression
Disease progression can manifest in any one of three ways:
Biochemical (PSA) Progression
The Prostate Cancer Clinical Trials Working Group 2 established specific PSA criteria that must all be met 1:
- PSA rise >2 ng/mL above the nadir value
- Rise of at least 25% over the nadir
- Confirmation by a second PSA measurement at least 3 weeks later 1
Radiographic Progression
- Development of new metastatic lesions on imaging (bone scan, CT, or MRI) 1
- Progression of existing metastatic disease by RECIST criteria 5
Clinical Progression
- Development or worsening of symptoms attributable to prostate cancer 1
- Symptomatic disease requiring regular opioid pain medications indicates progression 1
3. Continued Androgen Deprivation
- ADT must be continued indefinitely throughout CRPC treatment 2, 4
- CRPC does not mean androgen-independent disease; the androgen receptor remains active despite castrate testosterone levels 1, 6, 7
Clinical Subtypes of CRPC
Non-Metastatic CRPC (nmCRPC)
- Rising PSA with castrate testosterone 1
- No radiographic evidence of metastatic disease on conventional imaging 1
- Typically asymptomatic 2
Metastatic CRPC (mCRPC)
- Documented metastatic disease on imaging 1
- Can be asymptomatic/minimally symptomatic or symptomatic 1
- Symptomatic disease is defined as requiring regular opioid pain medications for cancer-related pain 1
Critical Pathophysiologic Understanding
Despite castrate serum testosterone, the androgen receptor remains active and continues to drive disease progression through multiple mechanisms 1, 6:
- Intratumoral androgen synthesis from adrenal precursors (DHEA, androstenedione) 8, 7, 9
- Adrenal production of androgens bypasses testicular suppression 9
- Tumor cells upregulate steroidogenic enzymes (CYP17) to produce androgens locally 8, 7
- This explains why second-generation AR inhibitors (abiraterone, enzalutamide) provide survival benefit by targeting these pathways 6, 7
Common Pitfalls to Avoid
Do not diagnose CRPC if:
- Testosterone is not confirmed to be <50 ng/dL—verify with laboratory testing first 3
- The patient has discontinued ADT—CRPC requires ongoing castration 4, 3
- PSA rise does not meet the specific criteria (>2 ng/mL above nadir, >25% increase, confirmed measurement) 1
Do not stop ADT when CRPC is diagnosed:
- ADT must be continued indefinitely as the backbone of all subsequent therapies 2, 4
- All FDA-approved CRPC treatments (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223) are studied and approved with concurrent ADT 4