What is the recommended treatment and dosage of Apalutamide (apalutamide) for non-metastatic castration-resistant prostate cancer?

Apalutamide for Non-Metastatic Castration-Resistant Prostate Cancer

Apalutamide 240 mg once daily with continued androgen deprivation therapy (ADT) is the recommended treatment for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) when PSA doubling time is ≤10 months. 1

Dosing and Administration

• Standard dose: 240 mg (four 60 mg tablets) taken orally once daily 1, 2
• Administration: Can be taken with or without food, as food does not cause clinically relevant changes in drug absorption 2
• Alternative administration: Tablets may be dispersed in applesauce without affecting bioavailability 2
• Continue ADT: Maintain ongoing androgen deprivation therapy to keep testosterone at castrate levels (<50 ng/dL) throughout treatment 3
• Duration: Continue until disease progression or unacceptable toxicity 1

Evidence Supporting Use

The FDA approval and NCCN Category 1 recommendation are based on the pivotal SPARTAN trial, which demonstrated:

• Metastasis-free survival: 40.5 months with apalutamide versus 16.2 months with placebo (HR 0.28; 95% CI 0.23-0.35; P<0.001) 1, 4
• Overall survival benefit: Final analysis at 52 months showed median OS of 73.9 months versus 59.9 months with placebo (HR 0.78; 95% CI 0.64-0.96; P=0.016), despite 19% crossover 1
• Time to symptomatic progression: Significantly longer with apalutamide (HR 0.45; 95% CI 0.32-0.63; P<0.001) 4
• Quality of life: Maintained throughout treatment in prespecified exploratory analysis 1

Patient Selection Criteria

Apalutamide is indicated for patients meeting all of the following:

• Non-metastatic disease on conventional imaging 1
• Castration-resistant (rising PSA despite castrate testosterone levels) 1
• PSA doubling time ≤10 months (critical eligibility criterion) 1, 4
• Continued castrate testosterone levels (<50 ng/dL) on ADT 1

Common Adverse Events and Monitoring

Most Frequent Side Effects

• Rash: 23.8% versus 5.5% with placebo—most common adverse event 1, 5, 4
• Fatigue: 30.4% versus 21.1% with placebo 5
• Hypertension: 24.8% versus 19.8% with placebo 5
• Fractures: 11.7% versus 6.5% with placebo 1, 4
• Hypothyroidism: 8.1% versus 2.0% with placebo 1, 4
• Falls: 15.6% versus 9.0% with placebo 5
• Weight loss: 16.1% versus 6.3% with placebo 5

Neurological Effects

• Mental impairment disorders: 5.1% versus 3.0% with placebo 5
• Dizziness: 9.3% versus 6.3% with placebo 5
• Seizure: Rare (0.2%) but requires monitoring 5

Required Monitoring

• Blood pressure: Monitor regularly due to hypertension risk 3
• Thyroid function: Check for hypothyroidism development 1
• Bone health: Assess fracture risk, consider bone-protective agents 1
• Cardiovascular status: Monitor for cardiac disorders 3
• Liver function: Assess hepatotoxicity risk 3
• Potassium levels: Monitor for hypokalemia 3

Pharmacokinetics and Drug Interactions

• Steady-state: Reached after approximately 4 weeks of daily dosing 2
• Half-life: Approximately 3 days at steady-state 2
• Metabolism: Primarily by CYP2C8 (40%) and CYP3A4 (37%) at steady-state 2
• Auto-induction: Apalutamide induces its own metabolism, with apparent clearance increasing from 1.3 L/h after single dose to 2.0 L/h at steady-state 2
• Active metabolite: N-desmethyl apalutamide contributes to clinical activity with similar exposure levels (AUC ratio 1.3) 2

Treatment Discontinuation

• Discontinuation rate: 10.6% with apalutamide versus 7.0% with placebo due to adverse events 4
• Common reasons: Rash, fatigue, or other intolerable side effects 1, 4

Special Populations

Older patients: Apalutamide demonstrated efficacy and tolerability across all age groups (<65-79, ≥80 years) with maintained quality of life, though adverse event rates may trend higher with increasing age 6

Clinical Pitfalls to Avoid

• Do not discontinue ADT: Continue androgen deprivation therapy indefinitely even during apalutamide treatment and subsequent disease progression 3
• PSA doubling time requirement: Only use in patients with PSADT ≤10 months, as this was the trial eligibility criterion 1, 4
• Rash management: Anticipate rash as the most common side effect and have management strategies ready 1, 5
• Fracture prevention: Consider bone-protective agents given 11.7% fracture rate 1, 4

Alternative Agents

Enzalutamide (160 mg daily) and darolutamide (600 mg twice daily) are equally effective Category 1 alternatives for nmCRPC with PSADT ≤10 months, with similar metastasis-free survival benefits but different side effect profiles 1