What are examples of androgen receptor inhibitors?

Androgen Receptor Inhibitors for Prostate Cancer

Direct Answer

The androgen receptor inhibitors currently used in prostate cancer treatment are enzalutamide, apalutamide, darolutamide, and abiraterone acetate (technically a CYP17A1 inhibitor that functions similarly to AR inhibitors). 1

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Mechanism of Action

Enzalutamide

• Enzalutamide competitively inhibits androgen binding to androgen receptors, inhibits nuclear translocation of androgen receptors, prevents DNA binding, and blocks coactivator recruitment. 1, 2
• The major metabolite N-desmethyl enzalutamide exhibits similar activity to the parent compound. 2
• Standard dosing is 160 mg daily. 1

Apalutamide

• Apalutamide functions as an androgen receptor signaling inhibitor with demonstrated survival benefits across multiple prostate cancer disease states. 1
• Standard dosing is 240 mg daily. 1

Darolutamide

• Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. 3
• The major metabolite ketodarolutamide exhibits similar in vitro activity to darolutamide. 3
• Standard dosing is 600 mg twice daily with food. 1, 3
• Darolutamide also functions as a progesterone receptor antagonist in vitro (approximately 1% activity compared to AR). 3

Abiraterone Acetate

• Abiraterone acetate is a nonsteroidal irreversible inhibitor of CYP17A1, which catalyzes the conversion of C21 progesterone precursors to C19 adrenal androgens, DHEA, and androstenedione. 1
• While technically not a direct AR inhibitor, it inhibits gonadal and extragonadal androgen synthesis, making it functionally similar to ADT but more potent. 1
• Standard dosing is 1000 mg daily plus prednisone 5 mg daily. 1

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Clinical Applications by Disease State

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

For fit patients with de novo mHSPC, triplet therapy with ADT + docetaxel + darolutamide is the most effective first-line regimen, achieving a 23-month overall survival gain (HR 0.68). 1, 4

Alternative triplet regimens include:

• ADT + docetaxel + abiraterone + prednisone (ESMO-MCBS score: 4) 1, 4
• ADT + docetaxel + apalutamide (median OS gain 16.4 months, HR 0.75) 4

For patients unable to tolerate triplet therapy, doublet regimens with novel hormone agents plus ADT are effective alternatives: 1, 4

• ADT + apalutamide (ESMO-MCBS score: 4, median OS gain 28.1 months, HR 0.65) 1
• ADT + enzalutamide (4-year OS gain 14%, HR 0.66-0.67) 1, 4
• ADT + abiraterone + prednisone (ESMO-MCBS score: 4, median OS gain 16.8-33 months, HR 0.60-0.66) 1, 4

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

All three second-generation AR inhibitors (apalutamide, enzalutamide, darolutamide) significantly improve metastasis-free survival when added to ADT in nmCRPC patients with rapidly rising PSA. 1, 5, 6

• Apalutamide and enzalutamide appear more efficacious for MFS (HR 0.85 and 0.86 vs darolutamide), with apalutamide showing the longest MFS gain. 4, 7
• Darolutamide demonstrates the most favorable tolerability profile with fewer adverse events. 5, 7, 8
• Enzalutamide achieved undetectable PSA levels in 24.2% of patients at 12 months versus 0.4% with placebo. 1

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

For first-line treatment of chemotherapy-naïve mCRPC with good performance status, options include abiraterone acetate plus prednisone, enzalutamide, or docetaxel. 1, 9

After progression on novel hormone therapy and docetaxel, cabazitaxel is the preferred next-line therapy based on the CARD trial (HR 0.64 for OS, p=0.008). 10, 9

Switching from abiraterone to enzalutamide (or vice versa) is no longer a preferred strategy due to demonstrated cross-resistance, with only 36% achieving any PSA decline and median PFS of 3.4 months. 10, 4

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Critical Safety Considerations

Enzalutamide

• Most frequently reported adverse events include fatigue, hypertension, adverse cardiovascular events, and mental-impairment disorders. 1
• Higher rates of hypertension and fatigue compared to other AR inhibitors. 8
• Mean terminal half-life is 5.8 days (range 2.8-10.2 days). 2

Apalutamide

• Rash of any grade occurs more commonly (27.1% versus 8.5% with placebo). 1
• Ischemic heart disease occurs in 4.4% versus 1.5% with placebo. 1
• Slightly higher rate of Grade 3+ adverse events and AE-related drug withdrawals compared to other AR inhibitors. 8

Darolutamide

• Darolutamide demonstrates the most favorable safety profile among the three second-generation AR inhibitors, with similar adverse event rates to placebo in many categories. 5, 7, 8
• Frequency of grade 3/4 events was similar between darolutamide and placebo arms in the ARASENS trial. 1
• Dose reduction required for severe renal impairment (eGFR 15-29 mL/min/1.73 m²) and moderate hepatic impairment (Child-Pugh Class B). 3

Abiraterone Acetate

• Monitor blood pressure and hepatic function every cycle due to risk of hypertension and grade 3-5 liver toxicity. 9
• Must be administered with prednisone 5 mg daily to mitigate mineralocorticoid excess. 1

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Treatment Selection Algorithm

For Newly Diagnosed mHSPC:

1. Fit patients with high-volume disease or visceral metastases: ADT + docetaxel + darolutamide (or abiraterone + prednisone) 1, 4
2. Patients unable to tolerate triplet therapy: ADT + novel hormone agent (apalutamide, enzalutamide, or abiraterone + prednisone) 1, 4
3. Vulnerable patients who cannot tolerate treatment intensification: ADT alone 1

For nmCRPC at High Risk of Metastasis:

1. Prioritize efficacy: Apalutamide or enzalutamide (superior MFS benefit) 4, 7
2. Prioritize tolerability: Darolutamide (most favorable safety profile) 5, 7, 8
3. Consider patient-specific factors: Cardiovascular comorbidities favor darolutamide; aggressive disease favors apalutamide/enzalutamide 5, 6

For mCRPC After Novel Hormone Therapy Failure:

1. Post-docetaxel and post-novel hormone therapy: Cabazitaxel is preferred over switching AR inhibitors 10, 9
2. PSMA-positive disease: Lutetium-177 PSMA-617 (after docetaxel and AR inhibitor) 1, 9
3. Bone-predominant disease without visceral metastases: Radium-223 1, 10, 9

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Critical Pitfalls to Avoid

Do not expect meaningful benefit from sequential use of abiraterone and enzalutamide due to well-documented cross-resistance mechanisms. 10, 4

Do not use radium-223 in patients with visceral metastases—it is contraindicated and ineffective in this setting. 10, 9

Do not delay chemotherapy in symptomatic mCRPC patients with good performance status—these patients derive the most benefit from docetaxel or cabazitaxel. 10, 9

Continue androgen deprivation therapy indefinitely throughout all subsequent treatments for castration-resistant disease. 9