Treatment Options for Castration-Resistant Prostate Cancer
Treatment Strategy Based on Metastatic Status
For patients with metastatic CRPC and good performance status who are chemotherapy-naïve, offer docetaxel 75 mg/m² every 3 weeks with prednisone 5 mg twice daily, abiraterone acetate 1000 mg daily plus prednisone 5 mg daily, or enzalutamide 160 mg daily as first-line options—all demonstrate survival benefit. 1, 2, 3
Non-Metastatic CRPC
For patients with non-metastatic CRPC:
Continue androgen deprivation therapy (ADT) with observation as the primary recommendation, as no treatment has demonstrated survival benefit or clinically meaningful delay in metastasis development in this population 1, 4
Offer enzalutamide or apalutamide as standard therapies for patients at high risk for developing metastatic disease, as these agents delay metastasis-free survival 1
Abiraterone plus prednisone may be offered to select patients unwilling to accept observation who cannot have standard therapies, though evidence in this setting is limited 1
Do not offer systemic chemotherapy or immunotherapy outside clinical trials for non-metastatic disease 1
Metastatic CRPC: First-Line Treatment Selection
The choice depends on symptom burden and performance status:
Asymptomatic or Mildly Symptomatic Patients (Good Performance Status)
Three equally valid first-line options exist 1, 2:
Abiraterone acetate 1000 mg daily plus prednisone 5 mg daily: Irreversible CYP17A inhibitor that blocks androgen synthesis. Monitor blood pressure and hepatic function every cycle due to mineralocorticoid excess causing hypertension, hypokalemia, and edema 1, 2
Enzalutamide 160 mg daily: Androgen receptor antagonist with median time to PSA progression of 37.2 months versus 3.9 months with placebo (HR 0.07). Monitor for seizures, hypertension, neutropenia, memory impairment, and cardiovascular events 1, 2
Docetaxel 75 mg/m² every 3 weeks with prednisone 5 mg twice daily: First agent to demonstrate survival benefit in mCRPC. Avoid in patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN due to increased risk of severe neutropenia and toxic death 1, 2, 3
Sipuleucel-T immunotherapy may be offered to asymptomatic patients as an alternative 1
Symptomatic Patients (Good Performance Status)
Docetaxel 75 mg/m² every 3 weeks with prednisone is the preferred option for symptomatic patients, as it provides both survival benefit and symptom palliation 1, 2, 4
- Do not administer docetaxel if neutrophil count <1500 cells/mm³ 3
- Prophylactic G-CSF may be used to mitigate hematological toxicity 3
- Monitor blood counts frequently as neutropenia may be severe 3
Poor Performance Status Patients
Palliative care is the primary recommendation 1, 4
Selected patients may receive:
- Abiraterone plus prednisone 1, 4
- Enzalutamide 1, 4
- Ketoconazole plus steroid 1, 4
- Radionuclide therapy 1, 4
Do not offer systemic chemotherapy or immunotherapy to patients with poor performance status outside clinical trials 1
Second-Line Treatment After Docetaxel Failure
Cabazitaxel 25 mg/m² every 3 weeks with prednisone plus primary prophylactic G-CSF is the preferred second-line option after docetaxel progression, demonstrating superior outcomes (median OS 15.1 vs 12.7 months, HR 0.70) 1, 2, 5, 6
Alternative second-line options if not previously used:
- Abiraterone acetate plus prednisone: OS gain of 4.6 months (14.8 vs 10.9 months, HR 0.65) 1, 2, 5
- Enzalutamide: OS gain of 4.8 months (18.4 vs 13.6 months, HR 0.63) 1, 2, 5
Important sequencing consideration: Cross-resistance exists between abiraterone and enzalutamide. If one was used first-line, switching to the other second-line shows diminished benefit compared to cabazitaxel 2, 5
Bone-Predominant Disease
Radium-223 dichloride is indicated for patients with symptomatic bone metastases without visceral disease, improving overall survival while specifically targeting bone disease 1, 2
Emerging Targeted Therapies
Lutetium-177 PSMA-617 is strongly recommended for patients with PSMA-positive disease who have failed both docetaxel and androgen pathway inhibitors, demonstrating superior outcomes with fewer adverse events 2, 7
Olaparib is indicated for patients harboring BRCA1, BRCA2, or ATM alterations who have progressed on prior androgen receptor axis inhibitor therapy, with survival benefit predominantly in BRCA-altered tumors 2
- Obtain somatic genetic testing early for all patients with mCRPC to identify actionable alterations 4
Bone Health Management
All patients with mCRPC and bone metastases should receive bone-protective agents 1, 4:
- Denosumab 120 mg subcutaneously monthly or zoledronic acid 4 mg IV every 3-4 weeks to reduce skeletal-related events 1
- Denosumab delays skeletal-related events longer than zoledronic acid, though neither prolongs survival 1
- Monitor for osteonecrosis of the jaw with both agents 1
Palliative Interventions
For symptomatic bone metastases:
- External beam radiotherapy (single 8 Gy fraction or 10 fractions of 3 Gy) for localized painful bone metastases 1
- Radioisotope therapy (strontium-89 or samarium-153) for widespread painful bone metastases 1
- Intravenous bisphosphonates for bone pain resistant to radiotherapy and conventional analgesics 1
Treatments to Avoid
Do not offer the following due to lack of benefit or excess toxicity 2:
- Bevacizumab
- Estramustine
- Sunitinib
Mitoxantrone may only be offered after discussion of limited clinical benefit and high toxicity risk 2
Critical Management Principles
Continue ADT indefinitely with LHRH agonist or antagonist throughout all subsequent treatments to maintain castrate testosterone levels (<50 ng/dL) 1, 4, 7
Manage patients in collaboration with dedicated palliative care services throughout the disease course 1
Consider clinical trial enrollment at all decision points, as the treatment landscape continues to evolve rapidly 1, 7