Which is better for treatment of prostate cancer: apalutamide, enzalutamide (Xtandi) or bicalutamide (Casodex)?

Comparison of Apalutamide, Enzalutamide, and Bicalutamide for Prostate Cancer Treatment

Enzalutamide is superior to both apalutamide and bicalutamide for the treatment of prostate cancer, with significantly better progression-free survival and overall survival outcomes. 1, 2

Efficacy Comparison

Enzalutamide vs. Bicalutamide

• Enzalutamide demonstrated significantly better progression-free survival compared to bicalutamide in the TERRAIN study, with median time to progression of 15.7 vs. 5.8 months (HR 0.44; 95% CI, 0.34-0.57) 1
• In the STRIVE trial, enzalutamide reduced the risk of progression or death by 76% compared to bicalutamide (HR 0.24; 95% CI, 0.18-0.32) 1, 3
• Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide in patients with both non-metastatic and metastatic CRPC 3
• Enzalutamide is designated as a category 1, preferred treatment option for patients without prior novel hormone therapy in the metastatic CRPC setting 1

Enzalutamide in Non-Metastatic CRPC

• In the PROSPER trial, enzalutamide improved metastasis-free survival over placebo (36.6 vs 14.7 months; HR 0.29; 95% CI, 0.24-0.35; P<0.0001) 1
• Median overall survival was longer with enzalutamide than placebo (67.0 vs 56.3 months; HR 0.73; 95% CI, 0.61-0.89; P=0.001) 1
• FDA approved enzalutamide for non-metastatic CRPC in July 2018 for patients with PSADT ≤10 months 1

Apalutamide in Non-Metastatic CRPC

• In the SPARTAN trial, apalutamide improved metastasis-free survival over placebo (40.5 vs 16.2 months; HR 0.28; 95% CI, 0.23-0.35; P<0.001) 1
• Median overall survival with apalutamide versus placebo was 73.9 vs 59.9 months (HR 0.78; 95% CI, 0.64-0.96; P=0.016) 1
• FDA approved apalutamide for non-metastatic CRPC in February 2018 1

Indirect Comparisons of Enzalutamide vs. Apalutamide

• Network meta-analyses show mixed results, with some suggesting apalutamide may have a slightly higher probability of more favorable MFS and OS compared to enzalutamide 4
• Other indirect comparisons found no significant difference in MFS between enzalutamide and apalutamide (HR 1.04,95% CI 0.78-1.37) 5
• A 2023 network meta-analysis indicated that enzalutamide and apalutamide were both superior to darolutamide and bicalutamide, with enzalutamide showing better therapeutic effects in both nmCRPC and mCRPC groups 6

Safety Profile Comparison

Enzalutamide

• Common adverse events include fatigue (33% vs 14% with placebo), hypertension (12% vs 5%), major cardiovascular events (5% vs 3%), and mental impairment disorders (5% vs 2%) 1
• Seizure is a rare but serious adverse event with enzalutamide 2
• No food restrictions and concurrent prednisone is permitted but not required 1, 2

Apalutamide

• Common adverse events include fatigue (30.4% vs 21.1%), hypertension (24.8% vs 19.8%), rash (23.8% vs 5.5%), diarrhea (20.3% vs 15.1%), and falls (15.6% vs 9.0%) 1, 7
• Unique adverse events include hypothyroidism (8.1% vs 2.0%) and rash 1, 7
• Mental impairment disorders occur in 5.1% of patients vs 3.0% with placebo 7

Bicalutamide

• Generally has fewer side effects than next-generation ARIs but significantly less efficacy 2
• May still be considered in some patients due to different side-effect profile and lower cost compared to enzalutamide 1, 2

Treatment Algorithm Based on Disease State

For Non-Metastatic CRPC with PSADT ≤10 months:

1. First choice: Enzalutamide - Category 1, preferred option with proven OS benefit and extensive safety data 1, 2
2. Second choice: Apalutamide - Category 1, preferred option with similar efficacy but potentially more adverse events including rash and hypothyroidism 1, 7
3. Third choice: Bicalutamide - Consider only if cost is prohibitive or specific contraindications to next-generation ARIs exist 1, 2

For Metastatic CRPC:

1. First choice: Enzalutamide - Category 1, preferred treatment option for patients without prior novel hormone therapy 1, 2
2. Second choice: Apalutamide - Consider if enzalutamide is not tolerated 6
3. Third choice: Bicalutamide - Significantly less effective but may be considered if cost is prohibitive 1, 3

Important Clinical Considerations

• Continue androgen deprivation therapy (ADT) with all these agents 2
• Monitor for specific adverse events: thyroid function with apalutamide; mental status and seizure risk with enzalutamide 1, 7
• Consider comorbidities when selecting therapy - cardiovascular disease may favor apalutamide, seizure history may favor apalutamide over enzalutamide 2, 7
• Cost considerations may influence treatment selection, as enzalutamide and apalutamide are significantly more expensive than bicalutamide 1, 2