Current and Emerging Treatments for Metastatic Castration-Resistant Prostate Cancer
For metastatic castration-resistant prostate cancer (mCRPC), the established life-prolonging treatments include abiraterone acetate plus prednisone, enzalutamide, docetaxel, cabazitaxel, radium-223, and lutetium-177 PSMA-617, with treatment selection based on prior therapy exposure, symptom burden, performance status, and disease characteristics. 1
First-Line Treatment Options for mCRPC
Chemotherapy-Naïve Patients with Good Performance Status
Docetaxel 75 mg/m² every 3 weeks with prednisone 5 mg twice daily is the standard first-line option, demonstrating improved overall survival and quality of life with moderate toxicity risk. 1, 2
Abiraterone acetate 1000 mg daily plus prednisone 5 mg daily is an alternative first-line option with demonstrated survival benefit and favorable benefit-harm balance. 1
Enzalutamide 160 mg daily is another first-line alternative showing improved survival, improved quality of life, and favorable benefit-harm balance. 1
For patients with predominantly bone metastases without visceral disease, radium-223 is a category 1 option that improves overall survival while specifically targeting symptomatic bone disease. 1, 3
Asymptomatic or Minimally Symptomatic Patients
Sipuleucel-T may be offered to asymptomatic or minimally symptomatic men, with demonstrated improved survival but unclear quality of life impact and low toxicity. 1
- This immunotherapy option is specifically indicated for patients without significant symptoms who can wait for the manufacturing process. 1
Second-Line Treatment After Docetaxel Failure
Post-Docetaxel Progression
Cabazitaxel 25 mg/m² every 3 weeks with prednisone plus primary prophylactic G-CSF is the preferred second-line option after docetaxel, demonstrating superior outcomes compared to switching between novel hormone therapies. 3, 4
The CARD trial definitively showed cabazitaxel improved radiographic progression-free survival (8.0 vs 3.7 months; HR 0.54) and overall survival (13.6 vs 11.0 months; HR 0.64) compared to switching from abiraterone to enzalutamide or vice versa. 3
Abiraterone acetate plus prednisone may be offered if not previously used, with demonstrated survival benefit in the post-docetaxel setting (median survival 15.8 vs 11.2 months; HR 0.74). 1
Enzalutamide is an alternative option for post-docetaxel patients not previously exposed to this agent. 1
Novel Hormone Therapy Sequencing
Cross-Resistance Between Abiraterone and Enzalutamide
Do not expect meaningful clinical benefit from switching between abiraterone and enzalutamide due to well-documented cross-resistance mechanisms—proceed directly to chemotherapy or PSMA-directed therapy instead. 3
If sequential novel hormone therapy is attempted despite limited evidence, the sequence of abiraterone followed by enzalutamide appears more favorable than the reverse sequence for progression-free survival (median time to second PSA progression 19.3 vs 15.2 months; HR 0.66). 5
PSA responses to second-line enzalutamide after abiraterone occurred in 36% of patients, whereas only 4% responded to abiraterone after enzalutamide. 5
Emerging Targeted Therapies
PSMA-Directed Radioligand 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, demonstrating superior outcomes with fewer adverse events. 1, 3
The VISION trial showed improved radiographic progression-free survival (8.7 vs 3.4 months; HR 0.40) and overall survival (15.3 vs 11.3 months; HR 0.62) when added to best standard of care. 1
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%). 3
PARP Inhibitors for DNA Repair Defects
Olaparib is indicated for patients with mCRPC harboring BRCA1, BRCA2, or ATM alterations who have progressed on prior androgen receptor axis inhibitor therapy, with survival benefit predominantly in BRCA-altered tumors. 1
- Updated PROfound trial analysis showed improved overall survival (19.1 vs 14.7 months; HR 0.69) in olaparib-treated patients with homologous recombination repair gene alterations. 1
Treatment Selection by Clinical Scenario
Poor Performance Status (ECOG 2+)
For patients with poor performance status, palliative care is the primary recommendation, with selected patients potentially receiving ketoconazole plus steroid or radionuclide therapy as palliative options. 1, 3
Abiraterone or enzalutamide may be considered only in highly selected poor performance status patients, though evidence is limited. 1, 3
Do not offer systemic chemotherapy or immunotherapy to poor performance status patients outside clinical trials. 1
Bone-Predominant Disease
Radium-223 is contraindicated in patients with visceral metastases and should only be used for symptomatic bone-predominant disease without visceral involvement. 1, 3
- Radium-223 can be combined with other systemic therapies or used as monotherapy depending on clinical context. 3
Combination Therapy Strategies
Intensification with Dual Androgen Pathway Inhibition
Apalutamide plus abiraterone-prednisone improved radiographic progression-free survival (24.0 vs 16.6 months; HR 0.70) compared to abiraterone-prednisone alone in chemotherapy-naïve mCRPC, though this combination is not yet standard practice. 6
- The most common grade 3-4 adverse event with combination therapy was hypertension (17% vs 10%). 6
Treatments to Avoid
Bevacizumab, estramustine, and sunitinib should not be offered due to demonstrated excess toxicity without survival benefit. 1
- Mitoxantrone may be offered only after discussion of limited clinical benefit (modest quality of life benefit without survival benefit) and high toxicity risk. 1
Critical Monitoring Requirements
For Docetaxel and Cabazitaxel
Monitor complete blood counts frequently as severe neutropenia may result in infection and death—do not administer to patients with neutrophil counts <1,500 cells/mm³. 4, 2
- Primary prophylaxis with G-CSF is recommended for all patients receiving cabazitaxel 25 mg/m². 4
For Abiraterone
Monitor blood pressure and hepatic function every cycle due to risk of hypertension (grade 3-5 in patients) and grade 3-5 liver toxicity (7% of patients). 1
Key Clinical Pitfalls
Do not delay chemotherapy in symptomatic patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 3, 2
Do not continue sequential novel hormone therapy expecting substantial benefit after progression on the first agent—the CARD trial definitively showed cabazitaxel superiority over this approach. 3
Continue androgen deprivation therapy (pharmaceutical or surgical) indefinitely throughout all subsequent treatments for mCRPC. 1