Definition of Castration-Resistant Prostate Cancer
Castration-resistant prostate cancer is defined as disease progression—evidenced by rising PSA and/or radiographic progression—that occurs despite maintaining castrate serum testosterone levels below 50 ng/dL (or <1.7 nmol/L). 1, 2, 3
Core Diagnostic Criteria
Testosterone Threshold:
- Serum testosterone must be confirmed at less than 50 ng/dL (<1.7 nmol/L) by laboratory testing 1, 3
- This castrate level must be maintained throughout the disease course, even when adding additional therapies 2, 3
- The 50 ng/dL cutoff is the established standard used across all major clinical trials that defined current treatment paradigms 3
Evidence of Disease Progression (at least one required):
- Biochemical (PSA) progression: PSA rise greater than 2 ng/mL above the nadir value, representing at least a 25% increase over nadir, confirmed by a second PSA measurement at least 3 weeks later 1, 2
- Radiographic progression: New metastatic lesions on bone scan, CT, or MRI imaging 1, 2
- Clinical progression: Worsening symptoms directly attributable to metastatic disease burden 1
Clinical Presentations
Non-Metastatic CRPC:
- Rising PSA with castrate testosterone levels 1, 2
- No radiographic evidence of metastatic disease on imaging 1
- Typically asymptomatic patients 1, 2
Metastatic CRPC (mCRPC):
- Documented metastatic disease on radiographic imaging with castrate testosterone 1, 2
- Can be asymptomatic, minimally symptomatic, or symptomatic 1
- Symptomatic disease is defined as requiring regular opiate pain medications for symptoms clearly attributable to documented metastases 1
Critical Clinical Considerations
Continuation of Androgen Deprivation:
- Patients must continue ADT with LHRH agonist/antagonist or maintain surgical castration status throughout all subsequent CRPC treatments 2, 3
- This maintains the castrate testosterone threshold even when disease progresses 3
Timing of Progression:
- Most patients with advanced prostate cancer progress to CRPC on average between 1-3 years after initiating castration therapy 1, 2
- This progression is inevitable and represents disease biology, not treatment failure 2
Antiandrogen Withdrawal:
- Consider evaluating for antiandrogen withdrawal response before confirming CRPC diagnosis, particularly if the antiandrogen produced a PSA decline lasting more than 3 months 3
Important Caveats
- Laboratory variation exists in testosterone measurement, but the 50 ng/dL threshold remains the standard for clinical decision-making and trial eligibility 3
- Intratumoral androgen levels may not correlate with serum testosterone and can be sufficient to stimulate tumor growth even at castrate serum levels, explaining why AR-mediated signaling persists in CRPC 3, 4
- PSA should not be the sole endpoint for monitoring; clinical and radiographic progression are more meaningful than PSA changes alone 5