Managing Abiraterone or Enzalutamide Resistance in mCRPC
For patients with mCRPC who have progressed on abiraterone (Zytiga) or enzalutamide (Xtandi), cabazitaxel is the preferred next-line therapy based on level 1 evidence, particularly if they have already received docetaxel. 1
Primary Treatment Algorithm After Novel Hormone Therapy Failure
If Prior Docetaxel + Prior Novel Hormone Therapy (Abiraterone or Enzalutamide)
Cabazitaxel is the category 1 preferred option based on the CARD trial, which demonstrated superior outcomes compared to switching between abiraterone and enzalutamide. 1, 2
Cabazitaxel 25 mg/m² every 3 weeks with prednisone/prednisolone 10 mg daily plus primary prophylactic G-CSF significantly improved radiographic progression-free survival (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=0.008) compared to switching to the alternate hormone therapy. 1, 2
This benefit was consistent regardless of whether the prior novel hormone therapy was given before or after docetaxel. 2
Switching from abiraterone to enzalutamide (or vice versa) is no longer a preferred strategy due to demonstrated cross-resistance between these agents and lack of evidence for meaningful survival benefit with sequential use. 1
If Prior Novel Hormone Therapy But No Prior Docetaxel
For patients with good performance status who progressed on abiraterone or enzalutamide without prior chemotherapy exposure:
Docetaxel-based chemotherapy is the standard recommendation, particularly for symptomatic disease or visceral metastases. 1
Cabazitaxel can be considered, though it is typically reserved for post-docetaxel settings. 1
The alternate novel hormone therapy (switching abiraterone to enzalutamide or vice versa) has limited efficacy due to cross-resistance mechanisms, though it remains an option for select patients. 1, 3
Specialized Treatment Options Based on Disease Characteristics
For PSMA-Positive Disease (Post-Docetaxel and Post-Novel Hormone Therapy)
Lutetium-177 PSMA-617 is strongly recommended for patients with PSMA-positive disease confirmed by imaging who have failed both docetaxel and androgen pathway inhibitors. 1, 4, 5
The TheraP trial demonstrated superior PSA response rates with Lu-177-PSMA-617 (66%) compared to cabazitaxel (37%), with fewer grade 3-4 adverse events (33% vs 53%). 1
Standard protocol consists of 4-6 cycles at 6-week intervals. 5
Pre-treatment requires PSMA-PET imaging confirmation, complete blood count, and renal/hepatic function assessment. 5
For Symptomatic Bone Metastases Without Visceral Disease
Radium-223 is a category 1 option for patients with good performance status, symptomatic bone-predominant disease, and no visceral metastases. 1
Radium-223 improves overall survival while specifically targeting bone metastases. 1
This can be used in combination with other systemic therapies or as monotherapy depending on clinical context. 1
Critical Considerations for Cross-Resistance
Do not expect meaningful benefit from sequential abiraterone-enzalutamide therapy due to well-documented cross-resistance mechanisms. 1, 6
Both agents target the androgen receptor axis through different mechanisms, but resistance to one typically confers resistance to the other. 1, 6
Limited retrospective data suggest abiraterone after enzalutamide progression yields only 10% PSA response rates with median time to progression of 15.4 weeks. 3
If sequential use is attempted, the sequence of abiraterone followed by enzalutamide appears more efficacious than the reverse, though neither is preferred over chemotherapy. 1
Performance Status-Based Approach
Good Performance Status (ECOG 0-1)
- First choice: Cabazitaxel if prior docetaxel and novel hormone therapy exposure. 1, 2
- Alternative: Docetaxel if no prior chemotherapy. 1
- PSMA-directed therapy if PSMA-positive and post-docetaxel. 1, 4
- Radium-223 specifically for symptomatic bone disease without visceral metastases. 1
Poor Performance Status (ECOG 2+)
For patients with poor performance status who progressed on novel hormone therapy after docetaxel:
Palliative care is the primary recommendation. 1
Selected patients may receive ketoconazole plus steroid or radionuclide therapy as palliative options. 1
Enzalutamide or abiraterone are options only for highly selected patients, though evidence is limited. 1
Monitoring Requirements During Treatment
Mandatory monitoring includes liver function tests, electrolytes (particularly potassium), blood pressure, and complete blood counts. 4, 7
Cardiac monitoring is essential for patients with pre-existing cardiovascular disease on any hormonal therapy. 7
PSA should be monitored regularly, but treatment decisions must not rely solely on PSA changes—radiologic imaging is required to detect true progression. 4, 7
For cabazitaxel, neutrophil monitoring is critical with primary G-CSF prophylaxis recommended at each cycle. 2
Common Pitfalls to Avoid
Do not continue sequential novel hormone therapy expecting substantial benefit—the CARD trial definitively showed cabazitaxel superiority over this approach. 1, 2
Do not use radium-223 in patients with visceral metastases—it is contraindicated and ineffective in this setting. 1
Do not delay chemotherapy in symptomatic patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 1, 2
Do not overlook clinical trial enrollment—for patients with limited standard options, clinical trials should be actively considered throughout the treatment course. 1