SUMMARY

• No prospective, randomized, head-to-head trials comparing the efficacy and safety of ERLEADA with darolutamide have been conducted.
• Apalutamide is an androgen receptor (AR) inhibitor that is structurally distinct from the AR inhibitor darolutamide.^1,2
• Results from a matching-adjusted indirect comparison (MAIC) study that utilized data from the phase 3 SPARTAN (ERLEADA plus androgen deprivation therapy [ADT] vs placebo plus ADT) and ARAMIS (darolutamide plus ADT vs placebo plus ADT) studies conducted in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have been reported.³
• Results from another MAIC study evaluating safety outcomes and metastasis-free survival (MFS) of darolutamide vs ERLEADA and enzalutamide utilizing data from the phase 3 studies conducted in patients with nmCRPC, ARAMIS, SPARTAN, and PROSPER (enzalutamide plus ADT vs placebo plus ADT), is described below.⁴
• A retrospective, real-world, descriptive analysis of treatment patterns and clinical outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) initiated on ERLEADA (n=940) vs darolutamide (n=239; stratified by receipt [n=65] or absence [n=174] of concomitant chemotherapy) was conducted. Achievement of a 90% prostate-specific antigen (PSA) reduction by 6 months among patients with baseline PSA >0.2 ng/mL included 77.1% (95% confidence interval [CI], 72.2-81.0) in the ERLEADA group, 68.0% (95% CI, 51.2-79.1) in the darolutamide plus chemotherapy group, and 58.2% (95% CI, 45.8-67.7) in the darolutamide without chemotherapy group. By 12 months postindex, the proportion of patients progressing to castration resistance was 8.6% (95% CI, 6.3-10.8), 26.0% (95% CI, 12.4-37.5), and 14.2% (95% CI, 7.3-20.6), respectively.⁵ 
• Results from a retrospective, real-world, observational chart review and retrospective, real-world prevalence study of potential drug-drug interactions that included comparison of ERLEADA and darolutamide in patients with nmCRPC have been reported.^6-8

CLINICAL DATA

No prospective, randomized, head-to-head clinical trials comparing the efficacy and safety of ERLEADA with darolutamide have been conducted.

ADDITIONAL DATA

MAIC Studies

Indirect treatment comparisons (ITCs) can be limited by cross-trial differences. By combining individual patient data (IPD) with published aggregate patient data, MAIC studies may reduce observed cross-trial differences and provide decision makers with timely comparative evidence.⁹

Chowdhury et al (2022)³ conducted an anchored MAIC study with a Bayesian framework that compared the efficacy and tolerability of ERLEADA plus ADT and darolutamide plus ADT in patients with nmCRPC.

The anchored MAIC was conducted using individual patient-level data from the phase 3 SPARTAN study (ERLEADA plus ADT vs placebo plus ADT) and aggregated patient data from the phase 3 ARAMIS study (darolutamide plus ADT vs placebo plus ADT) via the following steps:

• Application of inclusion/exclusion criteria from ARAMIS to SPARTAN prior to inclusion in MAIC
• Reweighting patients in SPARTAN to match aggregate baseline data of ARAMIS
• Recalculation of hazard ratios (HRs; for efficacy endpoints) and odds ratios (ORs; for tolerability endpoints) from the SPARTAN study based on the reweighted population
• Comparison of the reweighted SPARTAN data with ARAMIS data using a Bayesian framework with ADT as the common comparator across both studies

The primary efficacy endpoint was MFS. Secondary efficacy endpoints included PSA progression, progression-free survival (PFS), and overall survival (OS). Tolerability endpoints included the overall incidence of any adverse events (AEs) and serious AEs. Efficacy endpoints were estimated using HRs and 95% credible intervals (CrI), and tolerability endpoints were estimated using ORs. For the efficacy (except OS) and tolerability endpoints, the first interim analyses from both the SPARTAN and ARAMIS studies were used to compare ERLEADA and darolutamide. For OS, both the first and second interim analyses of the SPARTAN study were compared with the final analysis of the ARAMIS study.

In the first interim analysis, the median duration of follow-up for the SPARTAN and ARAMIS studies was 20.3 months and 17.9 months, respectively. Clinically relevant baseline characteristics were broadly comparable among patients in both studies (Table: Baseline Characteristics).

After matching, analysis of efficacy endpoints suggested that patients with nmCRPC treated with ERLEADA plus ADT had more favorable MFS, PFS, and PSA progression compared with those treated with darolutamide plus ADT. The OS benefit of ERLEADA plus ADT was similar to that of darolutamide plus ADT in the first and second interim analyses (Table: Efficacy Results in the ARAMIS and SPARTAN Studies and in the MAIC Study).

Analysis of tolerability endpoints suggested that both treatments have a similar tolerability profile based on incidence of any AE or serious AE (Table: Tolerability Results Before and After Matching and in MAIC).

Halabi et al (2021)⁴ conducted an anchored MAIC study that evaluated safety outcomes and MFS at primary analysis of patients with nmCRPC treated with darolutamide, ERLEADA, and enzalutamide in the ARAMIS, SPARTAN, and PROSPER studies, respectively. IPD from ARAMIS were selected and reweighted to match the inclusion criteria and baseline characteristics published in SPARTAN and PROSPER. The darolutamide vs ERLEADA MAIC matched on 7 covariates that included: age, PSA level and doubling time, Eastern Cooperative Oncology Group (ECOG) performance status, Gleason score, bone-sparing agent use, and prior surgery. For darolutamide vs ERLEADA, the effective sample size for the darolutamide and its placebo groups were 604 and 391, respectively, after matching. Of the AEs evaluated, there was no statistically significant difference between darolutamide and ERLEADA for dizziness, mental-impairment, hypertension, seizure, diarrhea, nausea, fatigue, and severe fatigue. Compared to ERLEADA, fall (risk difference [RD], -6.3%; OR, 0.6; Benjamini-Hochberg-adjusted p-value [p_BH]<0.05), fracture (RD, -6.2%; OR, 0.4; p_BH<0.05), and rash (RD, -16.0%; OR, 0.5; p_BH<0.0001) were significantly lower for darolutamide. Monitoring for AEs occurred more frequently in the SPARTAN study compared to the ARAMIS study and the impact of monitoring frequency on overall safety outcomes is unknown.^10,11 No MFS differences were observed before or after matching. The pre-match and post-match ratios of MFS HRs between darolutamide and ERLEADA were 1.29 (95% CI, 0.95-1.74) and 1.14 (95% CI, 0.83-1.58), respectively. Additionally, in the SPARTAN study the median treatment duration for the ERLEADA and placebo groups was 16.9 months and 11.2 months, respectively, and in the ARAMIS study was 14.8 months and 11.0 months in the darolutamide and placebo groups, respectively.^12,13

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 10 February 2025. Due to methodological differences and other potential limitations including scope, timing, study designs and statistical approaches, network meta-analyses and meta-analyses have been excluded in this response. Additional data beyond these parameters may be available in the literature.