What is the difference between castration-sensitive and castration-resistant prostate cancer?

Castration-Sensitive vs. Castration-Resistant Prostate Cancer: Definitions and Clinical Implications

Castration-resistant prostate cancer (CRPC) is defined as prostate cancer that progresses clinically, radiographically, or biochemically despite castrate levels of serum testosterone (<50 ng/dL), while castration-sensitive prostate cancer responds to testosterone suppression therapy.

Key Definitions

Castration-Sensitive Prostate Cancer

• Prostate cancer that responds to testosterone suppression through androgen deprivation therapy (ADT)
• Also referred to as "castration-naïve" (preferred term) or "hormone-sensitive" 1
• Characterized by:
  • Decreasing PSA levels in response to ADT
  • Regression or stabilization of metastatic lesions
  • Improvement in cancer-related symptoms

Castration-Resistant Prostate Cancer

• Defined by the AUA as "a rising prostate specific antigen level and/or radiographic evidence of prostate cancer progression despite medical or surgical castration" 1
• Specific criteria according to the Prostate Cancer Clinical Trials Working Group 2:
  • PSA progression: Rising PSA >2 ng/mL higher than nadir
  • The rise must be at least 25% over nadir
  • Confirmed by a second PSA at least three weeks later
  • Castrate testosterone levels (<50 ng/dL) must be maintained
  • With or without radiographic evidence of metastatic disease 1

Disease Progression Pathway

1. Initial Diagnosis: Advanced prostate cancer typically starts as castration-sensitive
2. ADT Response: Most patients initially respond to ADT with a median failure-free survival of about 1 year (range: 5.1-28.8 months) 1
3. Progression to CRPC: Despite continued ADT, most patients eventually develop resistance
   • Approximately one-third of patients with non-metastatic CRPC develop metastases within 2 years 1
   • High PSA and rapidly rising PSA are the two main risk factors for metastases 1

Clinical Subtypes of CRPC

1. Non-metastatic CRPC (M0 CRPC):

   • Rising PSA despite castrate testosterone levels
   • No radiographic evidence of metastases on conventional imaging
   • Typically confirmed with bone scan and pelvic-abdomen CT scan 1

2. Metastatic CRPC (mCRPC):

   • Further classified as:
     • Asymptomatic or minimally symptomatic: No symptoms or mild symptoms attributable to prostate cancer, not requiring regular narcotic medications 1
     • Symptomatic: Symptoms clearly attributable to metastatic disease requiring regular opiate pain medications 1

Treatment Implications

Castration-Sensitive Prostate Cancer

• Standard treatment: ADT via surgical or medical castration 2
• Intensification options:
  • Addition of docetaxel
  • Novel androgen receptor pathway inhibitors
  • Multimodal treatment with radiotherapy to the primary tumor 2

Castration-Resistant Prostate Cancer

• Continued ADT: All patients with CRPC should continue ADT indefinitely to maintain castrate testosterone levels 1, 3
• Additional therapies: Sequential addition of:
  • Secondary hormone therapies (abiraterone, enzalutamide, apalutamide)
  • Chemotherapies (docetaxel, cabazitaxel)
  • Immunotherapies
  • Radiopharmaceuticals
  • Targeted therapies 1, 3

Important Clinical Considerations

• The androgen receptor remains active even in CRPC, which is why ADT remains the backbone therapy 3
• Patients should not repeat therapies they've progressed on, with the exception of docetaxel rechallenge in specific circumstances 1
• For patients with bone metastases and CRPC, bone-modifying drugs are recommended 1
• Novel imaging techniques like axial skeleton MRI may have higher sensitivity than bone scans for detecting metastases in M0 CRPC 1

Treatment Sequencing

Treatment sequencing depends on:

1. Prior treatment exposures
2. Presence or absence of visceral disease
3. Patient symptoms
4. Potential side effects 1

The optimal sequence for delivering these agents is not fully established, requiring individualized approaches based on patient and disease characteristics.

Monitoring

• Regular PSA monitoring
• Maintaining testosterone at castrate levels (<50 ng/dL)
• Imaging procedures during follow-up only if results would change treatment management or in case of symptoms 1

Understanding the distinction between castration-sensitive and castration-resistant disease is crucial for optimal treatment selection and sequencing to maximize survival and quality of life for patients with advanced prostate cancer.