Choosing Between Enzalutamide, Apalutamide, and Abiraterone for Castration-Resistant Prostate Cancer
For treatment-naïve metastatic CRPC without prior docetaxel or novel hormonal therapy, enzalutamide is the preferred first-line agent based on superior overall survival, time to treatment switching, and PSA response compared to abiraterone, with apalutamide as an alternative if enzalutamide is contraindicated. 1
Treatment Selection Algorithm Based on Prior Exposures
The NCCN reorganized mCRPC treatment recommendations into four groups based on prior therapeutic exposures rather than lines of therapy 2:
Group 1: No Prior Docetaxel/No Prior Novel Hormone Therapy
- Enzalutamide is the preferred choice with demonstrated improvements in overall survival (RMST difference of 0.90 months at 4 years), time to treatment switching (1.95 months longer), and faster PSA response (3.57 months shorter time to response) compared to abiraterone 1
- These benefits are most pronounced in patients without prior docetaxel (1.14 months OS advantage) and those with PSA doubling time ≥3 months (2.23 months OS advantage) 1
- Apalutamide is an acceptable alternative with patient preference data showing 17.8% preference over enzalutamide, primarily due to less fatigue 3
- Abiraterone plus prednisone remains a standard option but requires mandatory corticosteroid co-administration and intensive monthly monitoring of liver function, potassium, phosphate, and blood pressure 4, 5
Group 2: Prior Novel Hormone Therapy/No Prior Docetaxel
- Avoid switching between abiraterone and enzalutamide due to cross-resistance and lack of OS benefit 2, 4
- The NCCN panel consensus states that abiraterone/enzalutamide crossover therapy is rarely effective 2
- For patients with primary resistance (no PSA decline, no radiological response), 55% of expert panels do not recommend switching to the alternative AR pathway inhibitor 2
- For acquired resistance (initial response followed by progression), 53% recommend switching only in a minority of selected patients 2
Group 3: Prior Docetaxel/No Prior Novel Hormone Therapy
- Either enzalutamide or abiraterone are appropriate first-line options 2
- Both agents demonstrated OS improvements in pivotal post-chemotherapy trials 2
- Choice should be guided by comorbidities and drug interaction profiles 2
Group 4: Prior Docetaxel/Prior Novel Hormone Therapy
- Cabazitaxel is the preferred Category 1 option based on CARD trial data showing radiographic PFS of 8.0 vs 3.7 months (HR 0.54, p<0.0001) and OS of 13.6 vs 11.0 months (HR 0.64, p=0.008) compared to switching between abiraterone and enzalutamide 2, 4
- The NCCN removed Category 1 labels from abiraterone and enzalutamide in this setting and moved them to "other recommended regimens" rather than "preferred regimens" 2
Optimal Sequencing Strategy When Both Agents Will Be Used
If sequential use of both agents is planned, start with abiraterone followed by enzalutamide rather than the reverse sequence 4, 6:
- Time to second PSA progression was 19.3 months for abiraterone→enzalutamide vs 15.2 months for enzalutamide→abiraterone (HR 0.66, p=0.036) 6
- PSA response to second-line enzalutamide was 36% vs only 4% for second-line abiraterone (p<0.0001) 6
- This sequencing strategy provides the greatest clinical benefit according to randomized crossover trial data 6
Non-Metastatic CRPC (M0 CRPC) Considerations
For M0 CRPC, all three agents are FDA-approved with demonstrated improvements in metastasis-free survival and OS 2:
- Apalutamide (approved February 2018) 2
- Enzalutamide (approved July 2018) 2
- Darolutamide (approved July 2019) - not included in original question but superior tolerability profile 2, 5
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Context
For patients with metastatic castration-sensitive disease, all three agents have indications 2, 7:
- Abiraterone (approved February 2018 for mHSPC) demonstrated improved OS over ADT alone in two trials 2
- Enzalutamide (approved December 2019 for mHSPC) 2
- Apalutamide (approved September 2019 for mHSPC) 2
Critical Adverse Event Profile Differences
Abiraterone-Specific Concerns:
- Requires mandatory prednisone 5mg twice daily 6
- Monthly monitoring mandatory: liver function, potassium, phosphate, blood pressure 4, 5
- Mineralocorticoid excess: hypertension, hypokalemia, fluid retention 5
- Chronic steroid exposure risks: hyperglycemia, weight gain, bone loss 5
- Overall discontinuation rate 12% 4
Enzalutamide-Specific Concerns:
- Fatigue/asthenia (most common reason for patient preference against it) 2, 3
- Seizure risk (contraindicated in patients with seizure history) 2
- QTc prolongation 2
- Multiple drug interactions 2
Apalutamide-Specific Concerns:
- Generally better tolerated with less fatigue than enzalutamide 3
- Patient preference studies show 17.8% preference over enzalutamide primarily due to fewer side effects 3
Common Pitfalls to Avoid
- Never switch from enzalutamide to abiraterone or vice versa after progression in the mCRPC setting—use cabazitaxel instead if docetaxel was already given 2, 4
- Never use abiraterone without corticosteroids without intensive monitoring and readiness to add mineralocorticoid receptor antagonist 5, 8
- Never repeat the same novel hormonal therapy after progression, except docetaxel rechallenge after progression on novel hormone therapy if docetaxel was given in castration-naive setting 2, 8
- Never extrapolate enzalutamide benefits to patients with prior docetaxel when choosing between enzalutamide and abiraterone—the OS advantage disappears in this subgroup 1
Specific Clinical Scenarios
Asymptomatic/Minimally Symptomatic mCRPC:
- 88% expert consensus recommends abiraterone or enzalutamide as first-line therapy 2
- Panel divided on preference: 39% abiraterone, 27% enzalutamide, 33% either 2
Symptomatic mCRPC:
- 77% consensus supports extrapolating trial results to symptomatic patients 2
- Consider docetaxel in 56% of patients with short response (≤12 months) to primary ADT 2