ERLEADA - Comparison of ERLEADA with Darolutamide

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
• MAIC Studies: Results are described below for anchored matching-adjusted indirect comparison (MAIC) studies that were conducted, utilizing 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) studies³ as well as utilizing data from SPARTAN, ARAMIS, and the phase 3 PROSPER (enzalutamide plus ADT vs placebo plus ADT) study⁴ in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). An unanchored MAIC study evaluating the safety profile of androgen receptor pathway inhibitors (ARPIs) in metastatic castration-sensitive prostate cancer (mCSPC), including ERLEADA and darolutamide, was also identified in the literature.⁵
• Retrospective Real-World Studies: Several analyses have compared the use of ERLEADA vs darolutamide in patients with ARPI-naïve mCSPC and nmCRPC.
  • Overall survival (OS), mCSPC⁶: 51% risk reduction of death through 24 months in the ERLEADA group vs darolutamide group (weighted hazard ratio [HR], 0.49;
    95% confidence interval [CI], 0.30-0.83; P=0.007]).
  • Undetectable prostate-specific antigen (PSA) response, mCSPC⁶: Undetectable PSA response was achieved in 71.0% vs 55.2% in the ERLEADA group vs darolutamide group, respectively (weighted HR, 1.44; 95% CI, 1.03-2.02; P=0.032).
  • PSA decline ≥90% (PSA90) response, mCSPC⁶: 49% higher rate of PSA90 response by 6 months in the ERLEADA group vs darolutamide group (weighted HR, 1.49;
    95% CI, 1.07-2.07; P=0.017]).
  • Treatment patterns and clinical outcomes, mCSPC⁷: PSA90 by 6 months among patients with baseline PSA >0.2 ng/mL included 77.1% (95% 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.
  • Central nervous system (CNS) outcomes, nmCRPC⁸: a numerically lower proportion of patients in the ERLEADA group vs darolutamide group experienced time-to-new onset of any CNS-related conditions at both 12-months (25.7% vs 31.4%) and 24-months (46.6% vs 54.6%) post-index. Patients in the ERLEADA group had a longer median time-to-new onset of any CNS-related conditions (29.2 months) vs the darolutamide group (21.3 months) and the rates of commonly observed new onset CNS-related conditions were lower in the ERLEADA group vs darolutamide group. 
• Several additional real-world analyses have evaluated various outcomes, including:
  • A retrospective, observational chart review of the DEAR-EXT study and its race subgroup analysis that included a comparison of ERLEADA and darolutamide treated patients with nmCRPC.^9,10
  • A retrospective cohort study that compared clinical use and outcomes of ERLEADA and darolutamide in patients with nmCRPC.¹¹ 
  • A retrospective cohort study assessed the duration of treatment and discontinuation rate of ERLEADA and ARPIs including darolutamide in patients with mCSPC.¹²
  • Studies that evaluated the prevalence and relevance of polypharmacy and potential drug-drug interactions with ARPIs including ERLEADA and darolutamide.^13,14
  • A comparison of prescription patterns and survival outcomes in patients with non-metastatic hormone-resistant prostate cancer using SEER-Medicare data.¹⁵
  • Adverse events (AEs) reported in patients with prostate cancer treated with medications including ERLEADA and darolutamide.^16-20
  • A retrospective, descriptive analysis that evaluated healthcare resource utilization and medical costs among patients with mCSPC initiated on ERLEADA vs darolutamide.²¹

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.²²

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 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 metastasis-free survival (MFS). Secondary efficacy endpoints included PSA progression, progression-free survival (PFS), and OS. Tolerability endpoints included the overall incidence of any AEs and serious AEs. Efficacy endpoints were estimated using HRs and 95% credible intervals (CrIs), 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.^23,24 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.^25,26

Retrospective Real-World Studies

Bilen et al (2026)⁶ conducted a real-world, retrospective, longitudinal comparative analysis of undetectable PSA response (PSA0.2; PSA ≤0.2 ng/mL) and PSA90 response by 6 months (ERLEADA group: n=714; darolutamide group: n=145) and OS response through 24 months (ERLEADA group: n=1460; darolutamide group: n=287) among patients receiving ERLEADA without docetaxel vs darolutamide without docetaxel in patients with mCSPC. Patient level-data were linked from electronic medical records (EMRs) from US community-based urology practices provided by Precision Point Specialty Analytics (PPS) and insurance claims data from Komodo Research Database (KRD). The study period spanned from January 2016 to April 2025 for PSA outcomes and January 2016 to June 2025 for OS evaluation (index date: August 5, 2022). Patient selection criteria included patients with ARPI-naïve mCSPC and for PSA analyses, a detectable PSA level (>0.2 ng/mL) in the most recent measurement within the 13-week period prior to and including the index date. Patients were excluded if they had prior use of an ARPI or other advanced treatment, such as chemotherapy, immunotherapy, poly adenosine diphosphate-ribose polymerase inhibitors, or radiotherapy, evidence of docetaxel use within -90/+30 days and ±90 days of index date (sensitivity analyses), or had another primary cancer. For the PSA analysis, patients were required to have ≥1 PSA measurement during the 13-week period prior to and including the index date, with the most recent measurement having a detectable PSA level (>0.2 ng/mL). Inverse probability of treatment weighting (IPTW) based on propensity score was used to balance baseline characteristics between the ERLEADA and darolutamide cohorts, with standardized differences of <10%. Clinical variables and the power calculation were adequately powered with probability >80% to detect true differences in PSA90 and OS, both of which were primary endpoints. PSA0.2 was exploratory.

In PSA analysis population, the median time from onset of metastasis to the index date was 1.9 months vs 2.0 months and concurrent ADT use was 98.1% vs 97.4% in the ERLEADA group vs darolutamide group, respectively. By 6 months, weighted Kaplan-Meier analysis showed that 74.6% vs 56.1% of patients achieved a PSA90 response in the ERLEADA group vs darolutamide group, respectively (49% higher in ERLEADA group; HR, 1.49; 95% CI, 1.07-2.07; P=0.017). Achievement of PSA0.2 response by 6 months was 71.0% vs 55.2% in the ERLEADA group vs darolutamide group, respectively (44% higher in ERLEADA group; HR, 1.44; 95% CI, 1.03-2.02; P=0.032).

In OS analysis population, the median time from onset of metastasis to the index date was 4.1 months vs 2.9 months and concurrent ADT use was 96.4% vs 95.6% in the ERLEADA group vs darolutamide group, respectively. By 24 months, 92.1% vs 85.8% of patients survived in the ERLEADA group vs darolutamide group, respectively (51% risk reduction of death in ERLEADA group; HR, 0.49; 95% CI, 0.30-0.83; P=0.007). The sensitivity analysis by 24 months yielded an HR of 0.49 (95% CI, 0.29-0.84; P=0.009).

Burbage et al (2025)⁷ conducted a retrospective, real-world, descriptive analysis of treatment patterns and clinical outcomes in patients with ARPI-naïve mCSPC initiated on ERLEADA (n=940) vs darolutamide (n=239; stratified by receipt [n=65] or absence [n=174] of concomitant chemotherapy) was conducted. Data was linked from PPS and KRD and the study period was from October 2015-October 2024. Concurrent ADT use was 88.6% vs 98.5% vs 92.5% and mean PSA level was 21.9 ng/mL vs 94.0 ng/mL vs 60.5 ng/mL in the ERLEADA group, darolutamide plus chemotherapy group, and darolutamide without chemotherapy group, respectively. Achievement of a 90% PSA reduction by 6 months among patients with baseline PSA >0.2 ng/mL included 77.1% (95% 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.

Lledo et al (2025)⁸ conducted a retrospective, real-world, descriptive analysis of central nervous system (CNS) outcomes among United States-based patients with nmCRPC, which included ERLEADA (n=253) and darolutamide (n=544) cohorts. Data was linked from PPS and KRD and the study period was from January 2016-August 2024. Concomitant use of ADT was not required for inclusion. The mean duration of the on-treatment observation period was 12.4 months for ERLEADA group and 14.0 months for the darolutamide group. A lower proportion of patients in the ERLEADA group experienced time-to-new onset of any CNS-related conditions at both 12-months (ERLEADA: 25.7%, darolutamide: 31.4%) and 24-months (ERLEADA: 46.6%, darolutamide: 54.6%) post-index. The patients in the ERLEADA group had a longer median time-to-new onset of any CNS-related conditions (29.2 months) compared with the darolutamide group (21.3 months) and the rates of commonly observed new onset CNS-related conditions (fatigue, falls, dizziness, pain, and weakness) were lower in the ERLEADA group compared with the darolutamide group.

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 22 July 2026. 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.