SAT-395 - Apalutamide Induced Hypothyroidism: A Spectrum of Presentation from Mild TSH Elevation to Severe Hypothyroidism in A Previously Stable Patient with Thyroidectomy

Background:
Apalutamide is an androgen receptor inhibitor with FDA indications for patients with metastatic castration-sensitive prostate cancer OR non-metastatic castration-resistant prostate cancer [1]. In the phase III SPARTAN trial which compared androgen deprivation therapy (ADT) + apalutamide versus ADT + placebo there was an increased adverse effect of hypothyroidism (8.1% vs. 2.0% respectively) [2]. A similar effect was seen in the phase III TITAN trial (6.5% vs 1.1% respectively) [3]. Apalutamide is an inducer of CYP3A4 and UDP-glucuronosyl transferase which can increase hepatic elimination of thyroxine [1].

Clinical

Case:
A 61-year-old man with post-surgical hypothyroidism after a thyroidectomy and RAI for papillary thyroid carcinoma presented to the clinic for routine follow up. He was previously stable on 2.5 mcg/kg daily of levothyroxine with a TSH of 0.26 (0.45 - 4.51 mIU/L) which is at goal for a thyroid cancer patient. On history, he reported adherence to his medication with proper administration. He noted that he was experiencing symptoms of weight gain (he gained 7 kg since last visit one year ago) and mild fatigue, however he is a marathon runner and was not impaired from participating in regular exercise due to his symptoms. Since his last visit he started treatment with apalutamide and radiation for a new diagnosis of prostate cancer with local lymph node metastases. Lab evaluation revealed a TSH of 68.8 (0.45 - 4.51 mIU/L), free T4 of 0.9 (0.9-2.2 ng/dL), total T4 of 3.8 (4.9-10.5 mcg/dL), T3 Uptake of 23% (L) (24%-39%), and an inadvertently stimulated thyroglobulin which was undetectable < 1 (goal of < 1.0 per 2025 ATA guidelines). His dose of levothyroxine was increased from 2.5 mcg/kg to 4.4 mcg/kg and repeat lab testing after one month resulted with a TSH of 40 (0.45 - 4.51 mIU/L), Free T4 1.4 (0.9-2.2 ng/dL), and total T4 5.2 (4.9-10.5 mcg/dL). Interestingly, despite a very high TSH his described symptoms were mild which has also been reported on previous case reports such as those from Florie Quattrochi et al [4]

We also present a second case of apalutamide induced hypothyroidism seen in a 67-year-old man who was previously euthyroid on no medications. He was started on apalutamide for prostate cancer and his TSH increased to 8.23 (0.45 -4.51 mU/L) with undetectable thyroglobulin and TPO antibodies.


Conclusion:
Urologists, endocrinologists, and oncologists should be aware that apalutamide has been associated with significant hypothyroidism in both previously euthyroid patients and hypothyroid patients on stable doses of thyroid supplementation. Patients with a prior total thyroidectomy are particularly susceptible to significant elevations of TSH and increased levothyroxine supplementation requirements that could be up to 4.4 mcg/kg per day.

References
[1] Apalutamide. Package insert.
[2] SPARTAN Trial
[3] TITAN Trial
[4] Quattrochi F, PMID: 40905521

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