Why does adding Erleada (apalutamide) to Eligard (leuprolide) increase fatigue?

Fatigue from Adding Apalutamide (Erleada) to Leuprolide (Eligard)

Fatigue is a common side effect when adding apalutamide (Erleada) to leuprolide (Eligard) therapy due to apalutamide's direct androgen receptor inhibition mechanism, which causes more profound androgen suppression and subsequent energy metabolism disruption.

Mechanism of Increased Fatigue

Apalutamide-related fatigue occurs through several mechanisms:

1. Enhanced Androgen Suppression

   • Apalutamide is a potent non-steroidal androgen receptor inhibitor that binds directly to the ligand-binding domain of the androgen receptor 1
   • When combined with leuprolide (which already reduces testosterone production), it creates a more complete androgen blockade
   • This profound hormonal suppression affects energy metabolism and contributes to fatigue

2. Direct Side Effect Profile

   • Clinical trials specifically identify fatigue as one of the most common adverse reactions with apalutamide
   • In the SPARTAN trial, fatigue was among the most frequently reported adverse events (≥10%) that occurred more commonly in apalutamide-treated patients compared to placebo 1

3. Metabolic Effects

   • Androgen deprivation affects muscle mass and metabolism
   • Apalutamide can cause changes in lipid metabolism, with hypertriglyceridemia occurring in 17% of patients (vs 12% on placebo) 1
   • These metabolic changes may contribute to energy depletion and fatigue

Comparative Incidence

The FDA label for Erleada (apalutamide) specifically lists fatigue as one of the most common adverse reactions (≥10%) that occurred more frequently in apalutamide-treated patients (≥2% over placebo) 1. This indicates that the addition of apalutamide to androgen deprivation therapy significantly increases fatigue compared to androgen deprivation therapy alone.

Management Strategies

For patients experiencing fatigue with combined apalutamide and leuprolide therapy:

1. Assessment

   • Rule out other causes of fatigue (anemia, hypothyroidism, depression)
   • Monitor for hypothyroidism, which occurs in 3.6% of apalutamide-treated patients versus 0.6% on placebo 1

2. Non-pharmacological approaches

   • Exercise has been beneficial in lowering fatigue levels in cancer patients 2
   • Begin with low levels of activity and gradually increase based on tolerance
   • Ensure adequate nutrition and hydration

3. Pharmacological interventions

   • Modafinil has shown promise for managing cancer-related fatigue in several studies 2
   • Methylphenidate may be considered for severe fatigue, though results are mixed 2
   • Consider L-carnitine supplementation if deficiency is suspected 2

4. Dose modification

   • For persistent severe fatigue, dose interruption or reduction of apalutamide may be necessary 3
   • Apalutamide was discontinued due to adverse reactions in 8-11% of patients in clinical trials 1

Important Considerations

• Quality of Life Impact: Despite side effects like fatigue, studies have shown that health-related quality of life is generally maintained in patients receiving apalutamide 3

• Benefit vs. Risk: The clinical benefit of adding apalutamide (improved survival) often outweighs the side effect of fatigue for most patients

• Monitoring Schedule: Regular assessment of fatigue and other symptoms during follow-up visits is recommended 3

• Comorbidity Management: Optimizing management of any comorbidities (cardiac, pulmonary, renal, hepatic, neurologic, endocrine dysfunction) may help reduce fatigue 2

Common Pitfalls to Avoid

1. Ignoring early signs of fatigue - Early intervention can prevent worsening

2. Failing to rule out other causes - Always check for anemia, hypothyroidism, and other treatable causes

3. Overlooking drug interactions - Combinations of medications (narcotics, antidepressants, antiemetics, antihistamines) may contribute to excessive drowsiness 2

4. Discontinuing therapy prematurely - Most side effects, including fatigue, can be managed without necessitating treatment discontinuation 3

By understanding the mechanism of increased fatigue with combined therapy and implementing appropriate management strategies, many patients can continue to benefit from apalutamide while maintaining an acceptable quality of life.