Definition
- Prostate cancer that has progressed despite castrate levels of testosterone (<50 ng/dL) achieved via surgical or medical castration.
- “Metastatic” indicates spread beyond the prostate (commonly to bone, lymph nodes, lungs, liver).
- “Castration‐resistant” means tumor growth continues even with androgen deprivation therapy (ADT).
Pathophysiology
- Tumor adapts to low testosterone by:
- Upregulating androgen receptor (AR) expression or mutations.
- Producing intratumoral androgens.
- Activating alternative growth signaling pathways.
Clinical Features
- Often asymptomatic initially; symptoms relate to metastases:
- Bone pain (most common).
- Pathologic fractures, spinal cord compression.
- Fatigue, weight loss.
- Lower urinary tract symptoms if local progression.
Diagnosis
- Castrate testosterone confirmed (<50 ng/dL).
- PSA progression (per PCWG3 criteria: ≥25% increase and ≥2 ng/mL above nadir).
- Radiologic progression (bone scan, CT/MRI).
- Clinical progression (symptoms).
Treatment Goals
- Extend overall survival.
- Delay disease progression.
- Reduce skeletal‐related events (SREs).
- Maintain quality of life.
First‐Line Options (Post‐ADT Progression)
(Usually given in addition to continued ADT to maintain castrate testosterone)
- AR pathway inhibitors:
- Abiraterone + prednisone.
- Enzalutamide.
- Apalutamide.
- Darolutamide (less CNS penetration).
- Chemotherapy:
- Docetaxel (in fit patients, especially with visceral metastases).
- Radiopharmaceuticals:
- Radium‐223 (bone‐only symptomatic metastases, no visceral disease).
Second‐Line & Later Options
- Cabazitaxel (post‐docetaxel failure; TROPIC trial showed OS benefit).
- Alternate AR inhibitor (if not used first‐line, but cross‐resistance common).
- PARP inhibitors (olaparib, rucaparib) in patients with BRCA1/2 or HRR gene mutations.
- ^177Lu‐PSMA‐617 for PSMA‐positive disease (per VISION trial).
Supportive Care
- Bone health:
- Denosumab (RANKL inhibitor) or zoledronic acid to reduce SREs.
- Calcium and vitamin D supplementation.
- Pain control (analgesics, radiotherapy for focal bone pain).
- Monitor for treatment‐specific toxicities.
Pharmacist Considerations
- Verify ongoing ADT with LHRH agonist/antagonist or orchiectomy status.
- Monitor for drug‐drug interactions (especially with CYP3A4 substrates/inhibitors for abiraterone, enzalutamide, cabazitaxel).
- Counsel on side effects and early reporting (e.g., diarrhea with cabazitaxel, hypertension with abiraterone, seizures with enzalutamide).
- Ensure labs for LFTs, CBC, electrolytes, and PSA are monitored at appropriate intervals.
- Advocate for genomic testing to identify HRR mutations for PARP inhibitor eligibility.
Key Takeaway:
mCRPC is a lethal stage of prostate cancer that progresses despite castration; management is multimodal, combining continued ADT with systemic agents (AR inhibitors, chemotherapy, targeted therapy) and supportive measures, with choice tailored to prior treatments, comorbidities, molecular profile, and patient preferences.
Metastatic Castration-Resistant Prostate Cancer (mCRPC)
- Definition:
Prostate cancer that has spread (metastatic) and progresses despite castrate levels of testosterone (< 50 ng/dL) achieved by ADT (surgical or medical). Tumor growth continues even though systemic androgen suppression is maintained. - Mechanism of resistance:
- Tumors adapt by upregulating androgen receptor (AR) signaling, increasing AR sensitivity, mutating AR, or synthesizing intratumoral androgens.
- Clinical features:
- Treatment options (beyond ADT, which is continued):
- Androgen receptor signaling inhibitors (ARSIs): abiraterone + prednisone, enzalutamide, apalutamide, darolutamide.
- Chemotherapy: docetaxel, cabazitaxel (for progression after docetaxel).
- Immunotherapy: sipuleucel-T (selected patients).
- Radiopharmaceuticals: radium-223 (bone-predominant disease, no visceral mets), lutetium-177–PSMA (targeted radioligand).
- PARP inhibitors: olaparib, rucaparib (for BRCA1/2, HRR mutations).
- Pharmacist’s role:
- Monitor drug-specific adverse effects (e.g., abiraterone → mineralocorticoid excess, hepatotoxicity; enzalutamide → fatigue, seizures; cabazitaxel → neutropenia, diarrhea).
- Evaluate for drug–drug interactions (especially with oral ARSIs and anticoagulants).
- Ensure supportive care: bone health (denosumab/zoledronic acid), management of skeletal-related events, pain control, cardiovascular risk.
- Assess genomic testing results for eligibility for PARP inhibitors or radioligand therapy.
Metastatic Castration-Sensitive Prostate Cancer (mCSPC)
- Definition:
Prostate cancer that has spread beyond the prostate (metastatic) but is still sensitive to androgen deprivation therapy (ADT). This means tumor growth remains driven by testosterone/androgens and responds to castration-level suppression (surgical or medical). - Clinical context:
- Patients present with metastases (bone, lymph nodes, visceral sites) at diagnosis or after local therapy.
- Unlike mCRPC (metastatic castration-resistant prostate cancer), these tumors have not yet developed resistance to ADT.
- Treatment principles:
- ADT (LHRH agonists/antagonists or orchiectomy) is the backbone.
- Treatment intensification is now standard:
- Abiraterone + prednisone
- Enzalutamide
- Apalutamide
- Darolutamide + docetaxel (triplet in high-volume disease)
- Choice depends on disease volume, patient comorbidities, performance status, and access.
- Pharmacist’s role:
- Monitor drug-specific toxicities (e.g., abiraterone → mineralocorticoid excess, hepatotoxicity; enzalutamide/apalutamide → fatigue, seizures, hypertension; docetaxel → neutropenia, neuropathy).
- Ensure adherence to oral oncolytics and proper administration (e.g., abiraterone on empty stomach).
- Manage supportive care (bone health, cardiovascular risk, hot flashes).