SUMMARY

• No prospective, randomized, head-to-head trials comparing the efficacy and safety of ERLEADA with bicalutamide have been conducted.
• The ongoing phase 3 ATLAS study is evaluating the efficacy and safety of ERLEADA plus a gonadotropin-releasing hormone agonist (GnRHa) compared to placebo plus a GnRHa in patients with high-risk, localized or locally advanced prostate cancer receiving treatment with primary radiation therapy (RT). In addition to GnRHa therapy, patients in the placebo group will receive bicalutamide for the first 4 (28-day) cycles of therapy.^1-3
• The ongoing phase 2 FORMULA-509 study is evaluating the efficacy and safety outcomes of adding 6 months of ERLEADA and abiraterone acetate plus prednisone (AAP) to the standard of care (SOC) of 6 months of GnRHa with salvage RT in patients with unfavorable features and a detectable prostate-specific antigen (PSA) post-radical prostatectomy (RP; N=345). Patients received salvage RT plus 6 months of GnRHa and randomization was to concurrent ERLEADA 240 mg once daily (QD) plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg. In the ERLEADA plus AAP group vs bicalutamide group, the 3 year progression-free survival (PFS) was 74.9% vs 68.5% (HR, 0.71; 90% CI, 0.49-1.03), respectively. For baseline PSA >0.5 (HR, 0.50; 90% CI, 0.30-0.86), the 3 year PFS was 67.2% vs 46.8%, respectively.⁴
  • Patient-reported health-related quality of life (HRQoL) was assessed using validated questionnaires at baseline, end of treatment, and 1 year after treatment completion. No differences in patient-reported hormonal function, fatigue, or mental status were reported between treatment arms at the end of treatment and 1 year after treatment.5
• A retrospective study comparing the efficacy of ERLEADA plus androgen deprivation therapy (ADT) vs bicalutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in Japan was identified in the literature.⁶ 
• Preclinical data comparing ERLEADA and bicalutamide have been reported.^7,8

CLINICAL DATA

ATLAS (NCT02531516) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of adding ERLEADA to GnRHa and external beam radiation therapy (EBRT) in patients with high-risk localized or locally advanced prostate cancer. The primary endpoint is metastasis-free survival (MFS). Patients will receive either ERLEADA 240 mg orally QD plus a GnRHa and placebo or bicalutamide 50 mg orally QD plus a GnRHa and placebo neoadjuvant to RT (cycles 1-2) and concurrent with therapy (cycles 3-4); treatment cycles are 28 days. Adjuvant to RT, patients will receive either ERLEADA 240 mg orally QD plus a GnRHa or placebo plus a GnRHa (cycles 5-30). Currently, the study is fully enrolled. Safety and efficacy results of the ATLAS study have not been published.^1-3

FORMULA-509 (NCT03141671) is an ongoing, phase 2, randomized, open-label, multicenter study evaluating the efficacy and safety outcomes of adding 6 months of ERLEADA and AAP to the SOC of 6 months of GnRHa with salvage RT in patients with unfavorable features and a detectable PSA post-RP (N=345). The primary endpoint is PSA PFS and secondary endpoint is MFS, determined by conventional imaging. Select inclusion criteria include PSA ≥0.1 post-RP and ≥1 unfavorable features: Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or high risk on Decipher test. Patients received salvage RT plus 6 months of GnRHa and randomization was to concurrent ERLEADA 240 mg QD plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg. Radiation to pelvic nodes was required for pN1 and optional for pN0. Patients were stratified by PSA at study entry (>0.5 vs ≤0.5) and pN0 vs pN1. A total of 29% of patients were pN1 and 31% of patients had PSA>0.5 ng/mL. The median follow-up was 34 months. In the ERLEADA plus AAP group vs bicalutamide group, the 3 year PFS was 74.9% vs 68.5% (HR, 0.71; 90% CI, 0.49-1.03). For baseline PSA >0.5 (HR, 0.50; 90% CI, 0.30-0.86), the 3 year PFS was 67.2% vs 46.8%. In the ERLEADA plus AAP group vs bicalutamide group, the 3 year MFS was 90.6% vs 87.2% (HR, 0.57; 90% CI, 0.33-1.01). In a pre-planned analysis by stratification factors, the ERLEADA plus AAP group was superior to the bicalutamide group for PSA >0.5 for PFS (HR, 0.50; 90% CI, 0.30-0.86; 2-sided P-value=0.03 and 3 year PFS 67.2% vs 46.8%) and MFS (HR, 0.32; 90% CI, 0.15-0.72; 2sided P-value=0.01 and 3 year MFS 84.3% vs 66.1%). Adverse events were consistent with the known safety profiles of each medication, with more rash and hypertension reported in the ERLEADA plus AAP group (incidence not reported).⁴

• Patient-reported HRQoL was also evaluated using validated questionnaires at baseline, end of treatment, and 1 year after treatment. Both treatment arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change, -15 bicalutamide group, -15 ERLEADA plus AAP group) and increases in PROMIS Fatigue (median change, 6 bicalutamide group, 7.4 ERLEADA plus AAP group) from baseline to end of treatment, which improved to near baseline at 1 year after treatment for both groups. Median Saint Louis University Mental Status Exam (SLUMS) score was within normal range at baseline, end of treatment, and 1 year after treatment for both groups. There was no significant difference in patient-reported hormonal function, fatigue, or mental status between groups at end of treatment and 1 year after treatment.⁵

PRECLINICAL DATA

Preclinical data comparing ERLEADA and bicalutamide have been reported. In a whole-cell binding assay, apalutamide was shown to bind androgen receptors (ARs) with 7- to 10-fold greater affinity than bicalutamide and competes for the same binding site in the ligandbinding pocket of the receptor. ERLEADA failed to stimulate proliferation of human prostate cancer cells and antagonized the proliferative effect of R1881, a synthetic androgen, whereas bicalutamide induced cell proliferation in a dose-dependent manner and only partially antagonized the effects of R1881. ERLEADA demonstrated greater antitumor activity than bicalutamide in a murine xenograft model of human castration-resistant prostate cancer. The antitumor activity of bicalutamide in this model was largely restricted to growth inhibition rather than tumor shrinkage with only 1 of 10 tumors exhibiting more than 50% regression. In contrast, 8 of 10 ERLEADA-treated tumors regressed by more than 50%, including 2 tumors that were no longer palpable.⁷

A preclinical study compared the effects of ERLEADA and bicalutamide on AR activation and cell proliferation in hormone-dependent and hormone-independent prostate cancer cell lines, in the presence or absence of testosterone. Three different prostate cancer cell lines (22Rv1, PC-3, DU145) were used to study the effect of ERLEADA and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, and levels of AR downstream proteins prostate-specific antigen and transmembrane serine protease 2 (TMPRSS2), under exposure to testosterone and/or hypoxia. The effects on autophagic flux and cell metabolism-related enzymes were also studied. Results demonstrated that ERLEADA had a stronger antiproliferative effect than bicalutamide. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolic enzyme levels was noted.⁸

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 06 February 2025.