What determines castration-resistant prostate cancer and how is it treated?

Castration-Resistant Prostate Cancer: Definition and Treatment

Definition of CRPC

Castration-resistant prostate cancer is defined as disease progression—either biochemical (rising PSA) or radiographic—that occurs despite maintaining castrate serum testosterone levels (<50 ng/dL or <1.7 nmol/L). 1, 2

Specific Biochemical Criteria

The Prostate Cancer Clinical Trials Working Group 2 established precise PSA criteria that must ALL be met: 1

• PSA rise >2 ng/mL above the nadir value
• PSA rise of at least 25% over the nadir
• Confirmation by a second PSA measurement at least 3 weeks later

Critical pitfall to avoid: Always verify testosterone is truly castrate (<50 ng/dL) before diagnosing CRPC—if testosterone is elevated, optimize or switch LHRH agents rather than labeling the patient as castration-resistant. 3, 2

Clinical Presentations

CRPC manifests in two distinct forms: 1, 2

• Non-metastatic CRPC: Rising PSA with castrate testosterone, no radiographic metastases, typically asymptomatic
• Metastatic CRPC (mCRPC): Documented metastatic disease on imaging, can be asymptomatic or symptomatic

Natural History

Most patients with advanced prostate cancer progress to CRPC within 1-3 years after initiating androgen deprivation therapy—this represents inevitable disease evolution, not treatment failure. 1, 2

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Treatment Approach

Foundational Principle: Continue ADT Indefinitely

The single most critical treatment principle is that androgen deprivation therapy (ADT) with LHRH agonist or antagonist MUST be continued indefinitely throughout all subsequent treatments for CRPC. 3, 4, 2

This is because castration-resistant disease does NOT mean androgen-independent disease—prostate cancer cells remain dependent on residual androgen signaling from non-gonadal sources including intratumoral synthesis and adrenal production. 3 All novel therapies for mCRPC were studied and approved with concurrent ADT as the backbone. 3

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Treatment by Clinical Scenario

Non-Metastatic CRPC (Index Patient 1)

For asymptomatic patients with non-metastatic CRPC, observation with continued ADT is the recommended approach. 2

• No treatment has demonstrated survival benefit or clinically meaningful delay in metastasis development 2
• Systemic chemotherapy or immunotherapy should NOT be offered outside clinical trials 2
• For select patients unwilling to accept observation, first-generation antiandrogens (flutamide, bicalutamide, nilutamide) or ketoconazole + steroid may be offered 2

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Metastatic CRPC Without Prior Docetaxel

Asymptomatic or Minimally Symptomatic (Index Patient 2)

For patients with good performance status who have not received docetaxel, offer abiraterone + prednisone, enzalutamide, or docetaxel as first-line options. 2, 4

• Abiraterone (CYP17 inhibitor) + prednisone demonstrated radiographic progression-free survival benefit 2
• Enzalutamide (androgen receptor antagonist) showed overall survival benefit 2, 4
• Docetaxel chemotherapy demonstrated overall survival advantage 2
• Sipuleucel-T immunotherapy may be considered but is NOT recommended as standard due to limited availability and practical constraints 2

For patients with BRCA1/2 alterations who have not received prior ARPI, the combination of PARPi + ARPI (talazoparib + enzalutamide, or olaparib/niraparib + abiraterone) is recommended. 4, 5

Symptomatic (Index Patient 3)

For symptomatic patients with good performance status and no prior docetaxel, offer docetaxel chemotherapy as the preferred option. 2

• Docetaxel provides both survival benefit and symptom palliation 2
• Alternative options include abiraterone + prednisone or enzalutamide 2
• Radium-223 is recommended for patients with symptomatic bone-only metastases without visceral disease 2, 4

Poor Performance Status (Index Patient 4)

For patients with poor performance status (ECOG 3-4), palliative care should be offered as the primary approach. 2

• For select patients where poor performance status is directly attributable to cancer burden, consider abiraterone + prednisone, enzalutamide, ketoconazole + steroid, or radionuclide therapy 2
• Systemic chemotherapy or immunotherapy should NOT be offered 2
• Sipuleucel-T is specifically contraindicated in this population 2

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Metastatic CRPC After Prior Docetaxel

Good Performance Status (Index Patient 5)

For patients with good performance status who received prior docetaxel, offer abiraterone + prednisone, cabazitaxel, or enzalutamide. 2, 4

The 2025 ASCO guideline provides the most current sequencing recommendations: 4

• If prior ARPI + docetaxel: Offer 177Lu-PSMA-617 (if PSMA-positive) or cabazitaxel chemotherapy
• If BRCA1/2 alterations present after prior ARPI: Offer PARPi monotherapy (olaparib) 4, 5
• If prior abiraterone before docetaxel: Offer cabazitaxel or enzalutamide 2

Critical evidence on cabazitaxel: The CARD trial (most recent high-quality evidence) demonstrated that cabazitaxel 25 mg/m² + prednisone + G-CSF showed superior radiographic PFS (8.0 vs 3.7 months, HR 0.54, p<0.0001) and overall survival (13.6 vs 11.0 months, HR 0.64, p=0.0078) compared to switching to alternative ARPI after progression on prior ARPI. 6

Poor Performance Status (Index Patient 6)

For patients with poor performance status who received prior docetaxel, palliative care is recommended. 2

• For highly selected patients, consider abiraterone + prednisone, enzalutamide, ketoconazole + steroid, or radionuclide therapy 2

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Special Populations and Molecular Considerations

BRCA1/2 and HRR Alterations

Early somatic genetic testing is recommended for all patients with mCRPC to identify actionable alterations. 4

• BRCA1/2 positive, ARPI-naïve: PARPi + ARPI combination (talazoparib + enzalutamide or olaparib/niraparib + abiraterone) 4, 5
• BRCA1/2 positive, post-ARPI: PARPi monotherapy (olaparib) 4, 5
• Treatment benefit may extend to select non-BRCA HRR alterations (CDK12, PALB2) 5

PSMA-Positive Disease

For patients who received prior ARPI and docetaxel with PSMA-positive disease, 177Lu-PSMA-617 radiopharmaceutical is recommended. 4

Microsatellite Instability-High/Mismatch Repair-Deficient

For select patients with MSI-H/dMMR tumors, pembrolizumab showed clinical efficacy. 4

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Bone Health Management

All patients with mCRPC and bony metastases should receive a bone-protective agent (zoledronic acid or denosumab) to reduce skeletal-related events. 4, 2

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Critical Clinical Pitfalls

1. Never discontinue ADT when CRPC develops—this is the most common and consequential error. Maintain castrate testosterone throughout all subsequent therapies. 3, 4

2. Verify castrate testosterone before diagnosing CRPC—inadequate testosterone suppression mimics castration resistance. 3, 2

3. Recognize cross-resistance between ARPIs—sequential use of abiraterone and enzalutamide shows limited clinical benefit due to shared resistance mechanisms. 7, 6 The CARD trial definitively showed cabazitaxel superiority over switching ARPIs. 6

4. Obtain molecular testing early—BRCA1/2 and HRR alterations fundamentally change treatment selection, and PARPi combinations show superior outcomes in this population. 4, 5

5. Consider performance status carefully—it determines treatment eligibility and should guide aggressive therapy versus palliative approaches. 2