What is the recommended use and patient selection criteria for Apalutamide in older adult males with a history of prostate cancer?

Apalutamide in Older Adult Males with Prostate Cancer

Apalutamide 240 mg daily plus androgen deprivation therapy (ADT) should be offered to older adult males with metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) with PSA doubling time ≤10 months, as it significantly improves overall survival and maintains quality of life regardless of age. 1, 2

Primary Indications and Patient Selection

Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Apalutamide is strongly recommended for men with mCSPC, including both de novo metastatic disease and those with recurrence after radical prostatectomy (RP) or radiation therapy (RT). 1

• The TITAN trial demonstrated that apalutamide plus ADT improved 24-month overall survival (82.4% vs 73.5%; HR 0.67, P=0.005) and radiographic progression-free survival at 24 months (68.2% vs 47.5%; HR 0.48, P<0.001) 2
• Benefits extend across disease volumes (high-volume and low-volume disease), Gleason scores, and metastasis stage at initial diagnosis 1
• The evidence quality is high with a strong strength of recommendation from ASCO guidelines 1

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Apalutamide is a Category 1, preferred treatment option for nmCRPC when PSA doubling time is ≤10 months. 1, 2

• The SPARTAN trial showed metastasis-free survival of 40.5 vs 16.2 months (HR 0.28; P<0.001) and final overall survival of 73.9 vs 59.9 months (HR 0.78; P=0.016) 1, 2, 3
• Time to symptomatic progression was significantly longer with apalutamide (HR 0.45; 95% CI, 0.32-0.63; P<0.001) 3
• Health-related quality of life was maintained throughout treatment 4, 3

Dosing and Administration

The recommended regimen is apalutamide 240 mg orally once daily with concurrent ADT (LHRH agonist or antagonist). 1, 5

• Apalutamide can be taken with or without food, as food does not cause clinically relevant changes in absorption 5
• Tablets may be dispersed in applesauce if swallowing is difficult, without affecting bioavailability 5
• Steady-state is achieved after 4 weeks of daily dosing 5
• Concurrent ADT must be continued throughout treatment to maintain castrate testosterone levels (<50 ng/dL) 2

Age-Specific Considerations for Older Adults

Apalutamide demonstrates consistent efficacy and tolerability across all age groups, including patients ≥80 years. 6

• Hazard ratios for overall survival favored apalutamide regardless of age: HR 0.57 (age <65), 0.70 (age 65-79), and 0.74 (age ≥80) in TITAN 6
• In SPARTAN, OS hazard ratios were 0.39 (age <65), 0.89 (age 65-79), and 0.81 (age ≥80) 6
• Quality of life was maintained across all age groups 6
• There is a potential trend toward increased adverse event rates with advancing age, but the drug remains well-tolerated 6
• No dose adjustments are required based on age alone (studied in patients 18-94 years) 5

Special Populations Requiring Consideration

Prior Docetaxel Exposure

Men with mCSPC previously treated with docetaxel appear to benefit with respect to radiographic progression-free survival, though evidence is not yet conclusive. 1

• At 22.7 months follow-up, apalutamide plus ADT showed significantly longer rPFS and OS compared with placebo 1
• The effect on rPFS was not statistically significant in the prior docetaxel subgroup, though it favored apalutamide 1
• Median OS among men previously treated with docetaxel could not yet be estimated at the time of guideline publication 1
• Discussions with patients should include the lack of long-term benefit data for those previously treated with docetaxel 1

Renal and Hepatic Impairment

No dose adjustments are required for mild to moderate renal impairment (eGFR 30-89 mL/min/1.73m²). 5

Required Monitoring During Treatment

Serial monitoring is essential to assess response and detect adverse events. 2

• PSA levels every 3-6 months 2
• Conventional imaging every 6-12 months 2
• Baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase, and thyroid function 2
• Blood pressure monitoring for all patients 2
• Monitor for rash (23.8% vs 5.5% placebo), fractures (11.7% vs 6.5%), and hypothyroidism (8.1% vs 2.0%) 1, 3

Critical Prerequisites Before Initiating Treatment

Confirm castrate testosterone levels (<50 ng/dL) before starting apalutamide. 2

• Calculate PSA doubling time to identify high-risk patients (≤10 months) for nmCRPC indication 1, 2
• Ensure no visible metastatic disease on conventional imaging for nmCRPC patients 2
• Verify concurrent ADT (LHRH agonist/antagonist or prior bilateral orchiectomy) is in place 2, 5

Drug Interactions and Contraindications

Apalutamide is a moderate to strong inducer of CYP3A4 and CYP2B6, requiring careful medication review. 5

• Co-administration decreased midazolam (CYP3A4 substrate) AUC by 92%, omeprazole (CYP2C19) by 85%, and S-warfarin (CYP2C9) by 46% 5
• Decreased exposure to P-gp substrates (fexofenadine AUC -30%) and BCRP/OATP1B1 substrates (rosuvastatin AUC -41%) 5
• May induce UGT, resulting in lower exposure to UGT substrate medications 5
• Strong CYP3A4 inhibitors (ketoconazole) may increase apalutamide exposure by 51% at steady-state 5

Cardiac Considerations

Apalutamide causes a concentration-dependent increase in QTcF interval. 5

• Maximum mean QTcF change from baseline was 12.4 ms (90% upper CI: 16.0 ms) 5
• Monitor for cardiovascular events, particularly in older patients with pre-existing cardiac conditions 6

Common Pitfalls to Avoid

• Never initiate apalutamide without confirming castrate testosterone levels (<50 ng/dL), as the drug is ineffective in non-castrate states 2
• Do not discontinue concurrent ADT during apalutamide treatment, as maintaining castrate levels is essential for efficacy 2, 5
• Avoid overlooking PSA doubling time calculation for nmCRPC patients, as the indication requires PSADT ≤10 months 1, 2
• Do not ignore potential drug interactions, particularly with narrow therapeutic index medications metabolized by CYP3A4, CYP2C19, or CYP2C9 5
• Monitor thyroid function regularly, as hypothyroidism occurs in 8% of patients 1, 3
• Assess fracture risk and consider bone-protective therapy, given the 11.7% fracture rate 1, 3