Androgen Deprivation Controls the Tumor
ADT lowers testosterone; sensitive tumor cells shrink and PSA falls.
- <50 ng/dL: Castrate testosterone target (clinical ADT threshold)
- ~15 ng/dL: Typical castrate level achieved (with LHRH agonist/antagonist)
- >90%: PSA response (of patients respond initially)
- 18–24 mo: Median time to CRPC (from ADT initiation)
Androgen deprivation therapy
Suppresses testicular testosterone to near-castrate levels.
Tumor response
Androgen-dependent cells undergo apoptosis, tumor regresses.
Clonal heterogeneity
A small resistant subpopulation already exists.
Rare resistant clones survive even the best initial response.
Selective Pressure Favors Resistant Clones
Months of low androgen select for AR-altered tumor subclones.
- ~30%: AR gene amplification (of CRPC tumors)
- ~15–20%: AR point mutations (enable low-androgen activation)
- ~20–30%: AR splice variants (AR-V7) (ligand-independent activity)
- GR, PI3K: Alternative pathways (AR-independent bypass signaling)
AR gene amplification
Extra AR copies boost sensitivity to trace androgens.
AR mutations
Altered receptor activates with weaker or alternate ligands.
AR-independent signaling
Bypass pathways sustain growth without androgen input.
Selection acts on pre-existing variants, not new mutations alone.
Growth Continues at Castrate Testosterone
Resistant subclones proliferate; sensitive cells stay suppressed.
- ~15 ng/dL: Testosterone during expansion (unchanged, still castrate)
- ~50%: Resistant fraction at crossover (population tipping point)
- 1.5–3×: Clonal doubling advantage (vs sensitive clone rate)
- High: Intratumoral heterogeneity (multiple resistant subclones coexist)
Subclonal expansion
Resistant lineages outcompete suppressed sensitive cells.
Testosterone independence
Growth no longer tracks circulating androgen level.
Imaging vs biology
Tumor volume may lag behind clonal shift.
The tumor is evolving before scans or labs show it.
PSA Rises Without Testosterone Rising
Rising PSA at castrate testosterone defines biochemical resistance.
- <3 mo: PSA doubling time (progression) (signals aggressive resistance)
- <50 ng/dL: Testosterone at PSA rise (confirmed castrate, unchanged)
- ≥2: Confirmatory PSA rises (consecutive tests, 1 week apart)
- PSA ≥2 ng/mL: CRPC definition threshold (per PCWG3 criteria)
The biochemical signature
PSA increase with testosterone flat defines CRPC.
Distinguishing from relapse causes
Confirmed castrate levels rule out testosterone escape.
Clinical monitoring
Serial PSA and testosterone tracked together closely.
PSA rise plus castrate testosterone equals resistance, not undertreatment.
CRPC Requires Second-Line Therapy
Further androgen suppression fails; new treatment classes are needed.
- Abi, Enza: Next-gen hormonal agents (abiraterone, enzalutamide)
- Docetaxel: Chemotherapy option (taxane-based cytotoxic therapy)
- PARP, Ra-223: Other targeted approaches (DNA repair, radiopharmaceutical)
- Maintained: ADT continuation (alongside second-line agents)
Next-generation hormonal agents
Block residual AR signaling more completely than ADT.
Chemotherapy
Cytotoxic agents target rapidly dividing resistant cells.
Targeted and radiopharmaceutical options
Additional mechanisms address specific resistance biology.
Castration alone can no longer control the disease.