SUMMARY

• Apalutamide may induce UDP-glucuronosyltransferase (UGT).¹ Because thyroid hormone (T4) is metabolized by UGT, induction of UGT may cause faster metabolism and clearance of T4 with subsequent increases in thyroid-stimulating hormone (TSH).²
• In SPARTAN, the phase 3 study in patients with non-metastatic castration-resistant prostate cancer (nmCRPC; N=1207), at the final analysis of overall survival (OS), which occurred after a median follow-up of 52 months, hypothyroidism was reported as an adverse event (AE) in 9.8% of patients in the ERLEADA group, 2.0% of patients in the placebo group, and 3.9% of patients in the crossover group. All were grade 1 or 2. The incidence of hypothyroidism with event rate per 100 patient-years of exposure were 5.1, 2.2, and 2.2 in the ERLEADA, placebo, and crossover groups, respectively.^3,4 Safety results, including hypothyroidism, were also previously reported in the second interim analysis for OS.⁵
• In TITAN, the phase 3 study in patients with metastatic castration-sensitive prostate cancer (mCSPC; N=1052), hypothyroidism was reported as an AE for 6.5% of patients in the ERLEADA group vs 1.1% of patients in the placebo group. All were grade 1 or 2.⁶

CLINICAL DATA

Phase 3 SPARTAN Study in Patients With nmCRPC

The phase 3, randomized, double-blind, placebo-controlled SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207).⁷ Patients were required to have a prostate-specific antigen doubling time of ≤10 months and confirmation of non-metastatic disease by blinded independent central review. Patients were randomized 2:1 to receive either ERLEADA 240 mg orally (PO) once daily (QD; n=806) or placebo QD (n=401). All patients received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration was 16.9 months in the ERLEADA group and 11.2 months in the placebo group.⁸ The final analysis of OS was conducted after a median follow-up of 52 months (median treatment duration for ERLEADA, placebo, and crossover groups: 32.9 months, 11.5 months, and 26.1 months, respectively).³

The incidences of hypothyroidism reported at the SPARTAN primary analysis and the final analysis for OS are shown in Table: Hypothyroidism in Phase 3 SPARTAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.⁷

In the SPARTAN primary analysis, hypothyroidism led to treatment discontinuation (n=1) and dose reduction (n=1) in the ERLEADA group; no patients required dose interruption.¹⁰ Treatment discontinuation, dose reduction, and dose interruption due to hypothyroidism were not observed in the placebo group. Hypothyroidism worsened in ERLEADA-treated patients already receiving thyroid replacement therapy.

Hypothyroidism was reported based on assessments of TSH every 4 months in the SPARTAN primary analysis.⁹ Generally, elevations in TSH occurred early in treatment; median time to first TSH elevation was 113 days in the ERLEADA group. Hypothyroidism was manageable with increases or initiation of thyroid replacement therapy.¹⁰

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

Phase 3 TITAN Study in Patients With mCSPC

The phase 3, randomized, double-blind, placebo-controlled TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).⁶ Patients were randomized 1:1 to receive either ERLEADA 240 mg PO QD (n=525) or placebo QD (n=527). All patients received a concomitant GnRH analog or had prior bilateral orchiectomy.¹¹ Patient baseline demographic and disease characteristics were well balanced, and there were no substantial differences between groups. The median treatment duration was 20.5 months in the ERLEADA group and 18.3 months in the placebo group.

The incidence of hypothyroidism is shown in Table: Hypothyroidism in Phase 3 TITAN Study. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.3.⁶

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 19 July 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN study in patients with nmCRPC and the phase 3 TITAN study in patients with mCSPC.