Does Xtandi (Enzalutamide) affect thyroid function?

Enzalutamide (Xtandi) and Thyroid Function

Enzalutamide (Xtandi) can cause hypothyroidism in some patients, with approximately 8% of patients developing hypothyroidism compared to 2% on placebo. 1

Effects of Enzalutamide on Thyroid Function

Enzalutamide is a novel androgen receptor (AR) signaling inhibitor used in the treatment of castration-resistant prostate cancer. It works by competitively inhibiting androgen binding, nuclear translocation of the AR, DNA binding, and coactivator recruitment.

The relationship between enzalutamide and thyroid function has been documented in clinical guidelines:

• In the PROSPER trial (evaluating enzalutamide in non-metastatic CRPC), hypothyroidism was identified as an adverse event of interest, occurring in 8.1% of patients receiving enzalutamide compared to 2.0% in the placebo group 1

• These hypothyroidism events were generally:

  • Grade 1 or 2 in severity
  • Identified early after starting enzalutamide treatment
  • Manageable with medical therapy

Monitoring Recommendations

For patients taking enzalutamide:

1. Baseline thyroid function testing before initiating treatment
2. Regular monitoring of TSH levels during treatment
3. Particular attention should be paid to monitoring thyroid stimulating hormone in individuals with known hypothyroidism 1

The American Thyroid Association recommends:

• Monitoring TSH levels every 6-8 weeks during dose titration
• Maintaining TSH within the reference range (0.45-4.5 mIU/L)
• Free T4 testing if TSH is abnormal 2

Clinical Significance and Management

The thyroid dysfunction observed with enzalutamide appears to be clinically significant but manageable:

• Hypothyroidism events were all grade 1 or 2 (mild to moderate)
• They were generally identified early in the treatment course
• They can be managed with appropriate medical therapy (thyroid hormone replacement)

For patients who develop hypothyroidism while on enzalutamide:

• Consider thyroid hormone replacement therapy (levothyroxine)
• Even with subclinical hypothyroidism, substitution with thyroid hormone should be considered if fatigue or other hypothyroid symptoms are present 1
• Continue to monitor TSH levels to ensure adequate replacement

Comparison with Other Androgen Deprivation Therapies

The effect of androgen deprivation therapy (ADT) on thyroid function has been studied more broadly:

• A cross-sectional study of 279 prostate cancer patients showed that ADT was associated with a statistically significant increase in TSH serum levels and a decrease in free T4 serum levels 3
• However, only about 2% of patients developed mild hypothyroidism, regardless of whether they were receiving ADT 3

Clinical Implications

1. Routine monitoring: Include thyroid function tests in the regular monitoring of patients on enzalutamide
2. Early intervention: Promptly address any thyroid abnormalities to prevent symptom development
3. Patient education: Inform patients about potential thyroid-related symptoms (fatigue, cold intolerance, weight gain, etc.)
4. Dose adjustments: No dose adjustments of enzalutamide are typically required for thyroid dysfunction; instead, manage the thyroid condition

Practical Approach

For patients starting enzalutamide:

1. Check baseline TSH and free T4 before treatment initiation
2. Monitor TSH every 1-3 months during the first year of treatment
3. For patients with pre-existing hypothyroidism, more frequent monitoring may be needed
4. If hypothyroidism develops, initiate thyroid hormone replacement while continuing enzalutamide

Conclusion

Enzalutamide has a documented effect on thyroid function, with hypothyroidism occurring in approximately 8% of treated patients. This side effect is generally mild to moderate and manageable with standard thyroid hormone replacement therapy. Regular monitoring of thyroid function is recommended, particularly in patients with pre-existing thyroid conditions.