What are the overall survival and progression-free survival benefits of androgen deprivation therapy (ADT) combined with docetaxel, abiraterone, enzalutamide, or apalutamide for metastatic prostatic acinar adenocarcinoma?

Overall Survival and Progression-Free Survival Benefits of Therapies for Metastatic Hormone-Sensitive Prostate Cancer

ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide each represent separate standards of care for metastatic hormone-sensitive prostate cancer, with each showing significant survival benefits compared to ADT alone. 1

Survival Benefits by Treatment Regimen

ADT Plus Docetaxel

• Most beneficial for patients with high-volume disease (HVD) as defined by CHAARTED criteria (four or more bone metastases with one or more outside spine/pelvis, and/or visceral disease) 1
• Not recommended for patients with low-volume disease (LVD) as there is no demonstrated overall survival benefit in this population 1
• Recommended regimen: six doses of docetaxel at 75 mg/m² administered every 3 weeks 1
• Advantages: relatively short treatment course and generally covered by insurance, reducing financial burden 1

ADT Plus Abiraterone

• Strongly recommended for men with high-risk de novo metastatic disease as defined by LATITUDE criteria 1
• May be offered to men with low-risk de novo metastatic disease per STAMPEDE data 1
• Recommended regimen: abiraterone 1,000 mg with prednisolone or prednisone 5 mg once daily until disease progression 1
• Associated with potential quality of life benefits compared to ADT alone for up to 24 months of follow-up 2

ADT Plus Enzalutamide

• Demonstrated short-term survival benefits (PSA progression-free, clinical progression-free, and overall) compared to ADT alone 1
• Recommended for both de novo metastatic disease and those who have received prior therapies such as radical prostatectomy or radiotherapy 1
• Recommended regimen: enzalutamide 160 mg per day with ADT 1
• Long-term benefits for patients previously treated with docetaxel remain unclear as final trial results are pending 1

ADT Plus Apalutamide

• Associated with significantly longer radiographic progression-free survival (rPFS) and overall survival compared to ADT plus placebo 1
• Beneficial across most subgroups including disease volume, Gleason score, and metastasis stage 1
• Recommended regimen: apalutamide 240 mg per day with ADT 1
• For patients previously treated with docetaxel, benefit on rPFS favored apalutamide but was not statistically significant 1

Comparative Efficacy and Prognosis

• A meta-analysis showed that adding new-generation anti-androgens (abiraterone, apalutamide, darolutamide, or enzalutamide) to ADT was associated with improved overall survival (pooled HR, 0.66; 95% CI, 0.61-0.71) 3
• Failure-free survival was significantly longer with combination therapy than ADT alone (pooled HR, 0.43; 95% CI, 0.39-0.47) 3
• Benefit-harm assessment suggests higher probabilities (>60%) for net clinical benefit with ADT plus abiraterone, enzalutamide, or apalutamide compared to docetaxel-containing regimens (<40%) 2
• Despite survival benefits, no systemic combination treatment showed clear HRQoL improvement over ADT alone 2

Safety Considerations

• All combination treatments are associated with increased rates of grade 3-5 adverse events compared to ADT alone 3, 2
• ADT plus docetaxel may cause a short-term decrease in health-related quality of life lasting 3-6 months 2
• The overall odds ratio of grade 3 or higher adverse events was significantly increased with combination therapy (pooled OR, 1.40; 95% CI, 1.13-1.74) 3

Clinical Implications and Decision-Making

• Currently, the use of these agents in any particular combination or series cannot be recommended due to lack of comparative data 1
• Evidence may support a general preference for ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies based on benefit-harm balance 2
• When selecting therapy, consider disease volume, performance status, comorbidities, toxicity profiles, cost, drug availability, and potential sequencing options 4

Common Pitfalls to Avoid

• Offering docetaxel to patients with low-volume disease, as evidence does not support survival benefit in this population 1
• Using micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the non-castrate setting, which is not supported by current guidelines 1
• Failing to discuss potential long-term benefits and costs of treatment, especially for enzalutamide and apalutamide where long-term data may still be evolving 1