What are the adverse effects of darolutamide (600 mg taken orally twice daily with food)?

Side Effects of Darolutamide

Darolutamide demonstrates a favorable safety profile with predominantly mild adverse events, most notably fatigue (12.1%), pain in extremity (5.8%), and rash (2.9%), with importantly similar fracture rates to placebo and no significant increase in serious adverse events compared to other androgen receptor inhibitors. 1

Most Common Adverse Events

Based on the pivotal ARAMIS trial data in non-metastatic castration-resistant prostate cancer (nmCRPC):

Adverse events occurring more frequently with darolutamide versus placebo:

• Fatigue: 12.1% vs 8.7%
• Pain in extremity: 5.8% vs 3.2%
• Rash: 2.9% vs 0.9%
• Fractures: 4.2% vs 3.6% (notably similar rates) 1

Grade 3-4 adverse events: 24.7% with darolutamide vs 19.5% with placebo 2

Favorable Safety Distinctions

Critical clinical advantage: Darolutamide shows a notably better safety profile compared to other androgen receptor inhibitors in its class:

• No significant increase in fractures (unlike apalutamide which showed 11% vs 6.5%)
• Lower rash incidence (2.9% vs apalutamide's 24%)
• No significant hypothyroidism signal (unlike apalutamide's 8% incidence)
• No significant cardiovascular adverse events or mental impairment disorders (unlike enzalutamide) 1, 2

Serious Adverse Events

• Serious adverse events: Occurred in 24% of patients in both darolutamide and placebo groups in ARAMIS 3
• Treatment-related deaths: One grade 5 event reported as death (not otherwise specified) 3

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Setting

When combined with ADT and docetaxel in the ARASENS trial:

Most common grade 3-4 adverse events:

• Hypertension: 4% (similar to placebo at 4%)
• Anemia: 3% (similar to placebo at 4%)
• Aspartate aminotransferase increase: 2% 3

Important finding: No cumulative adverse events over long-term treatment (median follow-up >3.5 years) 4

Feminizing Adverse Events

In the ARAMON monotherapy trial, feminizing adverse events were mostly grade 1/2 and occurred mainly during the first 6 months, attributed to the moderate 53% increase in serum testosterone at week 12 5. This is clinically relevant as darolutamide has low blood-brain barrier penetration, potentially resulting in less feminizing effects compared to other agents.

Drug Interactions and Metabolic Considerations

Key pharmacologic adverse event risk:

• 5-fold increase in rosuvastatin exposure when used concomitantly (BCRP, OATP1B1, OATP1B3 substrate) - requires dose adjustment 6
• 72% decrease in darolutamide exposure with rifampicin (strong CYP3A4 inducer) - avoid combination 6

Quality of Life Impact

Preserved quality of life: Multiple trials demonstrate maintenance of health-related quality of life with darolutamide treatment, with delayed time to deterioration in FACT-P total scores (HR 0.76) 3, 4. Pain progression is also delayed (HR 0.72) 3.

Clinical Pitfalls to Avoid

1. Do not assume class effect toxicity: Darolutamide has distinctly lower rates of rash, fractures, and CNS effects compared to apalutamide and enzalutamide
2. Monitor statin levels: Adjust rosuvastatin dose due to significant drug interaction
3. Avoid strong CYP3A4 inducers: Will substantially reduce darolutamide efficacy
4. Must take with food: Bioavailability increases 2.0-2.5 fold with food 6