Treatment Options for Metastatic Castration-Resistant Prostate Cancer
For patients with metastatic castration-resistant prostate cancer (mCRPC), continue androgen deprivation therapy indefinitely and offer abiraterone plus prednisone or enzalutamide as first-line therapy, with docetaxel chemotherapy as an alternative option depending on symptom burden and patient preferences. 1, 2, 3
Foundational Principle: Continue ADT Indefinitely
- Androgen deprivation therapy must be maintained throughout all subsequent treatments, regardless of castration-resistant status. 1, 2, 3
- Verify serum testosterone remains <50 ng/dL before diagnosing castration resistance and throughout all treatment phases. 2
- This is a critical pitfall to avoid—never discontinue ADT even when adding novel therapies, as maintaining castrate testosterone levels is essential for optimal outcomes. 2
First-Line Treatment Selection Algorithm
For Asymptomatic or Minimally Symptomatic Patients
Offer abiraterone acetate 1000 mg daily plus prednisone 5 mg twice daily OR enzalutamide 160 mg daily as preferred first-line options. 1, 2, 3
- Both agents demonstrate improved overall survival, quality of life, and favorable benefit-harm balance with Level I evidence. 1
- Sipuleucel-T immunotherapy may be offered to asymptomatic/minimally symptomatic men, though it has unclear quality of life impact and is only indicated in this specific population. 1, 4
- Critical caveat: Do not offer sipuleucel-T to symptomatic patients—it is contraindicated in this setting. 2
- Docetaxel 75 mg/m² every 3 weeks plus prednisone should also be discussed, particularly for patients with rapidly progressing disease, though it carries moderate toxicity risk. 1, 5
For Symptomatic Patients with Good Performance Status
Offer docetaxel 75 mg/m² every 3 weeks plus prednisone as first-line therapy, OR abiraterone/enzalutamide if chemotherapy is not appropriate. 1, 5
- Docetaxel demonstrates improved survival and quality of life with moderate toxicity risk (Level I evidence, Strength B). 1
- Do not use docetaxel 100 mg/m² in previously treated patients—this dose is associated with increased hematologic toxicity, infection, and treatment-related mortality. 5
- Prophylactic G-CSF may be used to mitigate hematological toxicities. 5
- Avoid docetaxel in patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN, as these patients are at increased risk for severe neutropenia and toxic death. 5
For Symptomatic Patients with Poor Performance Status (ECOG 3-4)
Offer palliative care as the primary recommendation—do not offer systemic chemotherapy or immunotherapy. 1
- Selected patients may receive abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or radionuclide therapy after careful discussion. 1
- Treatment in patients with poor performance status may delay access to end-of-life care and add unnecessary symptom burden. 1
Special Consideration: Bone-Predominant Disease
For patients with predominantly bone metastases, offer radium-223 dichloride, which demonstrates improved survival, quality of life, and favorable benefit-harm balance. 1, 2
- Radium-223 is specifically indicated for symptomatic bone metastases without visceral disease. 1, 2, 6
- All patients with mCRPC and bony metastases should receive bone-protective agents (zoledronic acid 4 mg every 3-4 weeks or denosumab). 1, 2, 3
- Denosumab delays skeletal-related events longer than zoledronic acid, though neither agent prolongs survival. 1
- Monitor serum calcium, oral health, and renal function (for zoledronic acid) in all patients receiving bone-protective agents. 1
Post-Docetaxel Treatment Options
For Patients with Good Performance Status After Docetaxel Failure
Offer cabazitaxel 25 mg/m² every 3 weeks plus prednisone, OR abiraterone/enzalutamide (if not previously used), OR lutetium-177 PSMA-617 for PSMA-positive disease. 1, 6, 3
- Cabazitaxel demonstrates improved survival with moderate to high toxicity risk (Level I evidence, Strength A). 1
- If abiraterone was used prior to docetaxel, offer cabazitaxel or enzalutamide. 1, 6
- Lutetium-177 PSMA-617 is strongly recommended for patients who failed both docetaxel and androgen pathway inhibitors with PSMA-positive disease, showing superior PSA response rates and fewer grade 3-4 adverse events. 6, 3
- Mitoxantrone may be offered with discussion of limited clinical benefit (modest quality of life benefit without survival benefit) and high toxicity risk. 1
For Patients with Poor Performance Status After Docetaxel
Offer palliative care as the primary recommendation. 1
- Selected patients may receive enzalutamide, abiraterone plus prednisone, ketoconazole plus steroid, or radionuclide therapy. 1
Agents to Avoid
Do not offer bevacizumab, estramustine, or sunitinib—these agents show no benefit and excess toxicity. 1, 2
- Estramustine specifically increases risk of clinically important toxicities without evidence of improved survival. 2
Alternative Hormonal Manipulations
- Ketoconazole or antiandrogens (bicalutamide, flutamide, nilutamide) may be offered with discussion of limited known clinical benefit (Level III evidence, Strength B). 1
- Second, third, and fourth-line hormone manipulations are options to seek short-term responses. 1
Survival Expectations with Modern Therapy
- Asymptomatic, chemotherapy-naïve patients with good performance status can expect median survival of 30-35+ months with modern androgen receptor pathway inhibitor therapy. 2
- Patients receiving sequential multiple lines of therapy can often achieve 5+ years of survival. 2
Critical Monitoring Requirements
- Regular monitoring of liver function, potassium levels, and blood pressure is mandatory with all hormonal therapies. 6
- Cardiac monitoring is required in patients with pre-existing cardiovascular disease. 6
- PSA response should be evaluated regularly, but treatment decisions should not be based solely on PSA changes—use radiologic imaging to detect progression. 6
- Monitor blood counts frequently with docetaxel, as neutropenia may be severe and result in infection; do not administer if neutrophil count <1500 cells/mm³. 5
Sequencing Considerations
- There is insufficient evidence to evaluate optimal sequences or combinations of therapies. 1, 3
- Sequential use of agents is reasonable in patients who remain candidates for further systemic therapy. 6
- Clinical trial enrollment should be considered throughout the disease course. 6
Essential Supportive Care
Palliative care should be offered to all patients with mCRPC, regardless of treatment status. 1, 3