ERLEADA®
(apalutamide)
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ERLEADA® (apalutamide)
Medical Information
ERLEADA - Hepatotoxicity
Last Updated: 05/22/2024
SUMMARY
- In SPARTAN, the phase 3 study in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; N=1207), treatment-emergent adverse events (TEAEs) related to hepatotoxicity were reported (Table: Treatment-Emergent Hepatotoxicity Events in the SPARTAN Study).1
, 2 - In TITAN, the phase 3 study in patients with metastatic castration-sensitive prostate cancer (mCSPC; N=1052), TEAEs related to hepatotoxicity were reported (Table: Treatment-Emergent Hepatotoxicity Events in the TITAN Study).3
,4 - In both the SPARTAN and TITAN studies, eligible patients were required to have adequate hepatic function (defined as serum aspartate transaminase [AST] and serum alanine transaminase [ALT] ≤2.5x upper limit of normal [ULN], and total serum bilirubin ≤1.5x ULN).5
,6
CLINICAL DATA
The SPARTAN study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC who had a prostate-specific antigen doubling time (PSADT) of ≤10 months and confirmation of non-metastatic disease by blinded independent central review (N=1207).2
Study Design/Methods
- Patients were randomized 2:1 to receive either ERLEADA 240 mg orally once daily (n=806) or placebo once daily (n=401).
- All patients in the study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a prior bilateral orchiectomy.
- Study inclusion criteria related to hepatic function:
- Adequate hepatic function (defined as serum AST and serum ALT ≤2.5x ULN, and total serum bilirubin ≤1.5x ULN).6
- Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median age of patients in both treatment groups was 74 years.
- The median treatment duration at primary analysis was 16.9 months in the ERLEADA group and 11.2 months in the placebo group.7
After unblinding of the study, 76 (19%) patients in the placebo group received therapy with ERLEADA plus ADT (crossover group). At the final analysis for OS, after a median follow-up of 52 months, the median treatment duration was 32.9 months in the ERLEADA group, 11.5 months in the placebo group, and 26.1 months in the crossover group.8
Safety
- AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
- Rates of treatment-emergent hepatotoxicity laboratory abnormalities at final analysis are reported in Table: Treatment-Emergent Hepatotoxicity Events in the SPARTAN Study.
| ERLEADA Group (n=803) | Placebo Group (n=398) | Crossover Groupb | |
|---|---|---|---|
| Increased ALT, % | |||
| Grade 1 | 1.0 | 0.8 | 0 |
| Grade 2 | 0.6 | 0.8 | 0 |
| Grade 3 | 0.1 | 0.3 | 1.3 |
| Grade 4 | 0 | 0 | 0 |
| Increased AST, % | |||
| Grade 1 | 1.0 | 1.0 | 0 |
| Grade 2 | 0.5 | 0.5 | 0 |
| Grade 3 | 0.4 | 0 | 1.3 |
| Grade 4 | 0 | 0 | 0 |
| Increased ALP, % | |||
| Grade 1 | 0.6 | 0.5 | 0 |
| Grade 2 | 0.5 | 0 | 0 |
| Grade 3 | 0.1 | 0 | 0 |
| Grade 4 | 0 | 0 | 0 |
| Increased bilirubin, % | |||
| Grade 1 | 0 | 0.3 | 0 |
| Grade 2 | 0.1 | 0 | 0 |
| Grade 3 | 0 | 0 | 0 |
| Grade 4 | 0 | 0 | 0 |
| Hyperbilirubinemia, % | |||
| Grade 1 | 0.1 | 0.3 | 0 |
| Grade 2 | 0.1 | 0 | 0 |
| Grade 3 | 0 | 0.3 | 0 |
| Grade 4 | 0 | 0 | 0 |
| Hepatoxicity events leading to dose reduction, % | |||
| Increased AST | 0 | 0 | 1.3 |
| Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute; TEAE, treatment-emergent adverse event. aTEAEs were those that occurred between the date of first dose of study drug and date of last dose of study drug plus 28 days. Patients were counted only once for any given event. The event experienced by the patient with the worst toxicity grade was used. bAfter study unblinding, patients in the placebo group were eligible for crossover into the ERLEADA group.2 | |||
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 Study in Patients with mCSPC (TITAN)
The TITAN study evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).3
Study Design/Methods
- Patients were randomized 1:1 to receive either ERLEADA 240 mg orally once daily (n=525) or placebo once daily (n=527).
- All patients in the study received a concomitant GnRH analog or had a prior bilateral orchiectomy.5
- Study inclusion criteria related to hepatic function:
- Adequate hepatic function (defined as serum AST and serum ALT ≤2.5x ULN, and total serum bilirubin ≤1.5x ULN).5
- Patient baseline demographic and disease characteristics were well balanced, and there were no substantial differences between groups. The median age of patients in the ERLEADA group and placebo group was 69 years and 68 years, respectively.
- The median treatment duration was 20.5 months in the ERLEADA group and 18.3 months in the placebo group.3 After unblinding of the study, 208 (39.5%) patients in the placebo group received therapy with ERLEADA plus ADT (crossover group). At the final analysis for OS, after a median follow-up of 44.0 months, the median treatment duration was 39.3 months in the ERLEADA group, 20.2 months in the placebo group, and 15.4 months in the crossover group.9
Safety
- AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3.
- Rates of treatment-emergent hepatotoxicity laboratory abnormalities at final analysis are reported in Table: Treatment-Emergent Hepatotoxicity Events in the TITAN Study.
| ERLEADA Groupb (n=524) | Placebo Group (n=527) | Crossover Groupc | |
|---|---|---|---|
| Increased ALT, % | |||
| Grade 1 | 3.2 | 5.1 | 1.9 |
| Grade 2 | 1.0 | 1.7 | 0 |
| Grade 3 | 0.6 | 1.1 | 0 |
| Grade 4 | 0 | 0 | 0 |
| Increased AST, % | |||
| Grade 1 | 2.5 | 4.9 | 2.4 |
| Grade 2 | 0.6 | 2.1 | 0 |
| Grade 3 | 0.4 | 1.1 | 0 |
| Grade 4 | 0 | 0 | 0 |
| Increased ALP, % | |||
| Grade 1 | 1.9 | 1.9 | 0.5 |
| Grade 2 | 1.1 | 1.7 | 0 |
| Grade 3 | 0.4 | 2.5 | 1.0 |
| Grade 4 | 0 | 0 | 0 |
| Hyperbilirubinemia, % | |||
| Grade 1 | 0.2 | 0.2 | 0 |
| Grade 2 | 0.4 | 0.2 | 0 |
| Grade 3 | 0 | 0 | 0 |
| Grade 4 | 0.2 | 0 | 0 |
| Hepatotoxicity events leading to dose interruption, % | |||
| Increased ALT | 1.0 | 0.9 | 0 |
| Increased AST | 0.8 | 1.3 | 0 |
| Increased ALP | 0.4 | 0 | 0 |
| Hyperbilirubinemia | 0.2 | 0 | 0 |
| Hepatic cirrhosis | 0.2 | 0 | 0 |
| Hepatic failure | 0 | 0.2 | 0 |
| Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute; TEAE, treatment-emergent adverse event. aTEAEs were those that occurred between the date of first dose of study drug and date of last dose of study drug plus 30 days. Patients were counted only once for any given event. The event experienced by the patient with the worst toxicity grade was used. bOne patient assigned to the ERLEADA group withdrew consent before treatment. cAfter study unblinding, patients in the placebo group were eligible for crossover into the ERLEADA group.3 | |||
Literature Search
A literature search of MEDLINE®
References
| 1 | Data on File. Apalutamide. SPARTAN Clinical Study Report. Janssen Research & Development, LLC. EDMS-ERI-205435292; 2020. |
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