What are Androgen Receptor Inhibitors (ARIs) for prostate cancer?

Androgen Receptor Inhibitors (ARIs) for Prostate Cancer

Androgen Receptor Inhibitors (ARIs) are a class of second-generation antiandrogen medications—specifically enzalutamide, apalutamide, and darolutamide—that directly block androgen receptor signaling and have become standard treatments for advanced prostate cancer, demonstrating significant survival benefits in both hormone-sensitive and castration-resistant disease. 1

Mechanism of Action

ARIs work through multiple mechanisms to block androgen signaling more completely than traditional androgen deprivation therapy (ADT):

• Apalutamide binds directly to the androgen receptor's ligand-binding domain, inhibits nuclear translocation, prevents DNA binding, and blocks AR-mediated transcription, ultimately decreasing tumor cell proliferation and increasing apoptosis 2
• Enzalutamide functions as a competitive inhibitor of androgen binding while also blocking nuclear translocation, DNA binding, and coactivator recruitment 1, 3
• Darolutamide operates through similar AR inhibition pathways, though with potentially different pharmacologic properties 1

These agents are fundamentally different from 5-alpha-reductase inhibitors (5-ARIs like finasteride and dutasteride), which only block conversion of testosterone to dihydrotestosterone and are used primarily for benign prostatic hyperplasia and prostate cancer chemoprevention, not treatment of established cancer 1

Clinical Indications and Evidence

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

For newly diagnosed metastatic hormone-sensitive disease, ARIs combined with ADT significantly improve survival:

• The TITAN trial demonstrated apalutamide plus ADT reduced death risk by 35% (median OS not reached vs 52.2 months; HR 0.65) with 68% of patients achieving undetectable PSA levels 1, 2
• The ARASENS trial showed darolutamide plus ADT/docetaxel reduced death risk by 32.5% (HR 0.68) with similar toxicity profiles between arms 1
• Enzalutamide in the PEACE-1 trial combined with ADT plus docetaxel improved both OS (HR 0.82) and radiographic PFS (HR 0.54) 1

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

All three ARIs are FDA-approved for nmCRPC based on dramatic improvements in metastasis-free survival:

• Enzalutamide, apalutamide, and darolutamide all demonstrated large MFS benefits in placebo-controlled trials, with enzalutamide and apalutamide showing slightly superior efficacy compared to darolutamide (HR 0.71 and 0.68 respectively vs darolutamide) 4, 5, 6
• Apalutamide reduced PSA to undetectable levels in 38% of nmCRPC patients versus 0% with ADT alone 2

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

• Enzalutamide benefits both pre- and post-chemotherapy mCRPC patients, though pre-chemotherapy use shows better radiographic PFS improvement (HR 2.11) 5, 6

Comparative Effectiveness

While no head-to-head trials exist, indirect comparisons suggest clinically meaningful differences:

• Enzalutamide and apalutamide appear equivalent in efficacy for nmCRPC (HR 0.97), both superior to darolutamide for MFS 5
• Darolutamide may have better tolerability with lower discontinuation rates (30.4% vs 40.8% for enzalutamide and 46.0% for apalutamide) and lower progression to metastatic disease (17.7% vs 28.3% and 27.8%) in real-world cohorts 7
• Enzalutamide and darolutamide showed equivalent OS benefits in mHSPC (HR 1.19; no significant difference) 5

Adverse Event Profiles

The choice between ARIs should be guided by individual patient comorbidities and toxicity profiles:

• Apalutamide has higher rates of rash (27.1% vs 8.5% placebo), Grade 3+ adverse events, and drug withdrawal due to adverse events compared to other ARIs 1, 6, 7
• Enzalutamide causes significantly higher rates of hypertension and fatigue, which may be problematic in elderly patients with cardiovascular comorbidities 6
• Darolutamide demonstrates the most favorable tolerability profile with lower discontinuation rates (risk reduction 27.4% vs enzalutamide, 39.1% vs apalutamide) 7
• Falls occur more frequently in elderly patients, particularly those ≥75 years (19% vs 8% in younger patients) receiving apalutamide 2

Clinical Decision Algorithm

Select ARI based on this hierarchy:

1. For patients with cardiovascular disease or hypertension: Choose darolutamide over enzalutamide to avoid exacerbating hypertension 6, 7

2. For patients with dermatologic conditions or concerns about rash: Avoid apalutamide (27.1% rash rate) and prefer darolutamide or enzalutamide 1, 6

3. For elderly patients (≥75 years) at high fall risk: Consider darolutamide given lower overall discontinuation rates, though all ARIs increase fall risk 2, 7

4. For maximum efficacy in nmCRPC: Enzalutamide or apalutamide show slightly better MFS than darolutamide, but darolutamide's superior tolerability may result in better real-world outcomes 5, 7

5. For triplet therapy in de novo metastatic disease: Combine ARI with ADT plus docetaxel per ARASENS trial data showing 32.5% mortality reduction 1

Important Clinical Considerations

• Pre-treatment evaluation must include cardiovascular risk assessment, metabolic screening, and medication interaction review before initiating ARIs 8
• PSA monitoring shows 68% of mHSPC patients on apalutamide achieve undetectable PSA (<0.2 ng/mL) versus 32% on ADT alone 2
• Drug interactions require careful review as ARIs can affect metabolism of other medications 8
• Cardiac effects: Apalutamide increases QTcF by mean 12.4 ms, requiring baseline ECG consideration in high-risk patients 2