How do you choose between abiraterone (Zytiga) and darolutamide (Nubeqa) for a patient with high-volume metastatic hormone-sensitive prostate cancer, given the differences in trial design and evaluation points?

Choosing Between Abiraterone and Darolutamide for High-Volume mHSPC

For patients with high-volume metastatic hormone-sensitive prostate cancer who are fit for chemotherapy, triplet therapy with ADT + docetaxel + darolutamide is the preferred choice based on the most robust survival data from ARASENS, while ADT + docetaxel + abiraterone from PEACE-1 is an equally valid alternative, with selection between them based primarily on side effect profiles and cost considerations rather than efficacy differences. 1

Why Direct Comparison Is Problematic

You are correct that head-to-head trials are lacking, and the trial designs differ substantially:

• PEACE-1 (abiraterone): Enrolled only de novo metastatic patients, used a 2×2 factorial design, and showed a 1-year overall survival gain (HR 0.75; 95% CI 0.59-0.95) in the triplet arm versus ADT + docetaxel 1

• ARASENS (darolutamide): Enrolled 86.1% de novo patients (allowing 13.9% recurrent disease), used a standard randomized design, and demonstrated a 2-year overall survival improvement with 4-year OS of 62.7% versus 50.4% (HR 0.68; 95% CI 0.57-0.80) 1, 2

The different follow-up durations, patient populations, and trial methodologies make direct numerical comparisons of survival gains misleading 3.

Current Guideline Recommendations

Both triplet regimens are NCCN Category 1, preferred options for patients with metastatic castration-sensitive prostate cancer, with use strongly encouraged for high-volume de novo disease in chemotherapy-fit patients 1.

The 2023 NCCN Guidelines explicitly state that triplet therapies should be prioritized over doublet therapy (ADT + docetaxel alone) for high-volume disease, as both PEACE-1 and ARASENS demonstrated superior overall survival compared to ADT + docetaxel 1.

Practical Selection Algorithm

Step 1: Confirm Patient Eligibility for Triplet Therapy

• High-volume disease (visceral metastases or ≥4 bone lesions with ≥1 beyond vertebral bodies/pelvis) 1
• Good performance status (ECOG 0-1) and fit for docetaxel chemotherapy 4
• De novo metastatic presentation strongly favors triplet therapy 3

Step 2: Choose Between Abiraterone and Darolutamide Based on:

Favor Darolutamide if:

• Patient has cardiovascular risk factors or pre-existing cardiac disease (darolutamide shows lower rates of cardiovascular adverse events and fatigue compared to other androgen receptor pathway inhibitors) 2, 5
• Desire to avoid mandatory corticosteroid therapy (darolutamide does not require concurrent prednisone) 2
• Patient preference for twice-daily dosing with food is acceptable 2

Favor Abiraterone if:

• Cost is a major consideration (generic abiraterone at $9,745.56 for 6 months versus darolutamide at $72,768) 2
• Patient can tolerate corticosteroids and prefers once-daily dosing 2
• Alternative low-dose administration with food (250 mg with low-fat breakfast) is desired for cost savings 1, 6

Step 3: Monitoring Requirements

For Abiraterone + Prednisone:

• Monthly monitoring (at least initially) of liver function tests, serum potassium, phosphate levels, and blood pressure 1, 6
• Watch for mineralocorticoid excess (hypertension, hypokalemia, peripheral edema) 1
• Common adverse events include hypertension (22%), hypokalemia (17%), peripheral edema (28%), and fatigue (39%) 1

For Darolutamide:

• Serial PSA every 3-6 months and conventional imaging every 6-12 months 2
• No specific electrolyte or mineralocorticoid monitoring required 2
• Adverse events similar to placebo, with notably lower fatigue rates (5.6% vs 8.1% placebo) 5

Quality of Life Considerations

Abiraterone demonstrates measurable QoL benefits with 37% risk reduction in pain intensity progression, 53% reduction in fatigue (paradoxically, despite higher reported fatigue rates), and 15% reduction in overall QoL deterioration compared to ADT alone 7. However, these data compare abiraterone doublet to ADT alone, not triplet therapy.

Darolutamide shows favorable tolerability with lower discontinuation rates due to adverse events (6.1% vs 9.0% placebo) and lower fatigue incidence than placebo 5.

A systematic review found that benefit-harm assessment showed higher probabilities (>60%) for net clinical benefit with androgen receptor pathway inhibitors over docetaxel-containing regimens when considering QoL impacts 8. However, this analysis predates the triplet therapy data.

Common Pitfalls to Avoid

• Do not use ADT + docetaxel doublet therapy alone for high-volume mHSPC when patients are fit for triplet therapy, as this is now considered suboptimal 1

• Do not switch between abiraterone formulations (original vs fine-particle) or between abiraterone with different steroids upon disease progression 1

• Do not avoid corticosteroids with abiraterone without careful monitoring and readiness to add mineralocorticoid receptor antagonist or steroid if side effects develop 1

• Do not repeat the same novel hormonal therapy after progression, with the exception of docetaxel rechallenge after progression on a novel hormone therapy if docetaxel was given in the castration-naive setting 1

Bottom Line for Clinical Practice

In the absence of head-to-head data, both triplet regimens are considered equivalent in efficacy for high-volume mHSPC. 1 The choice should be driven by:

1. Cardiovascular risk profile (favor darolutamide if high risk) 2, 5
2. Cost and access (favor generic abiraterone if cost-prohibitive) 2
3. Patient preference regarding dosing schedule and corticosteroid use 2
4. Tolerability concerns (darolutamide has more favorable adverse event profile) 5

For patients who cannot tolerate chemotherapy, doublet therapy with ADT + abiraterone or ADT + darolutamide (without docetaxel) remains appropriate, though triplet therapy is preferred when feasible 1, 5.