Enzalutamide (Xtandi™; Astellas Pharma and Pfizer) in combination with androgen deprivation therapy (ADT) showed better efficacy than darolutamide (Nubeqa®; Bayer) + ADT for treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC).[1]
This finding is based on new matching-adjusted indirect comparison (MAIC) results comparing relative efficacy outcomes between enzalutamide + ADT and darolutamide (Nubeqa®; Bayer) + ADT in patients diagnosed with mHSPC.
These findings published in Future Oncology, can help inform treatment decisions in clinical practice.[1]
Among the study results, researchers found that treatment with enzalutamide was associated with statistically significant lower risk of radiographic progression, death and progression to castration resistance compared to darolutamide.[2]
“In the absence of direct head-to-head trials, MAIC analyses offer a valid method for data comparison, minimizing biases derived from differences in study designs and populations,” explained Andrew J. Armstrong, MD, ScM, Lead Author, Director of Research at the Center for Prostate & Urologic Cancers, Duke Cancer Institute, Durham, NC, and ARCHES primary investigaton.
“Applying this method to the ARCHES and ARANOTE Phase 3 trials showed that for patients with mHSPC, enzalutamide in combination with androgen deprivation therapy slowed disease progression or death compared to darolutamide plus ADT and extended the time to castration resistance. The differences in efficacy were statistically significant. Given multiple ARPI options are currently available, the findings from this study, along with other patient factors, can help support shared decision-making around treatment for patients with mHSPC,” Armstrong added.
Multiple androgen receptor pathway inhibitors (ARPis) are recommended in clinical practice guidelines alongside ADT for the treatment of mHSPC.[2][3] However, differences in trial designs and patient populations can make direct comparisons on their respective efficacy profiles extremely challenging.
While head-to-head randomized trials remain the gold standard for comparing treatments, the value of MAICs (matching-adjusted indirect comparisons) is increasingly being recognized as a method to evaluate clinical trial results and derive respective efficacy and safety conclusions. MAIC methodology weights different patient populations to ensure comparable baseline characteristics and minimize bias.[1]
Statistical comparison
Matching-adjusted indirect comparison (or MAIC) is a statistical method that allows for indirect comparisons between separate trials. MAIC allows for indirect efficacy comparisons by using individual patient data from one trial to match the distribution of effect modifiers (such as some baseline characteristics) reported for another trial. This allows us to adjust for between-trial imbalances (such as differences in baseline characteristics), thus minimizing population differences. This form of weighted adjustment, similar to propensity matching, allows for a fair comparison of the trial datasets and outcomes in a more restricted subset of patients that are matched for important baseline confounders, or patient characteristics that are associated with treatment outcomes like progression free or overall survival.[1]
MAIC analyses are widely used in health technology assessments by insurers, regulators within specific countries such as the UK’s NICE, health plans, and providers to make inferences about comparative effectiveness of specific treatments in the absence of true gold standard head-to-head randomized comparisons. These weighted treatment comparisons can be assessed for both the experimental group but also against a similar placebo treated group if that exists to ensure fair and balanced comparisons. Baseline confounders should be pre-specified before looking at the data and accounted for in the comparison. [1]
First MAIC in mHSPC
This is the first MAIC study in mHSPC that compares the efficacy of enzalutamide to darolutamide using results from the Phase 3 ARCHES and ARANOTE trials, which used a common comparator (placebo + ADT) as an anchor.
The MAIC study assessed the relative efficacy of enzalutamide in combination with ADT compared to darolutamide in combination with ADT in patients with mHSPC. Data were compared from two global, double-blind Phase 3 trials – ARCHES: where patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg administered orally once daily) and ADT or placebo and ADT, and ARANOTE: where patients with mHSPC were randomly assigned 2:1 to receive darolutamide (600 mg administered orally twice daily) and ADT or placebo and ADT. Individual patient data from ARCHES (enzalutamide vs placebo; N=1150) were adjusted to match the baseline characteristics of ARANOTE (darolutamide vs placebo; N=669), with weights applied to ensure comparable, thus minimizing biases due to population differences and enabling indirect comparison of the treatments.[1]
In both ARCHES and ARANOTE, radiographic progression-free survival (rPFS) was the primary endpoint, while secondary endpoints included time to castration resistance, time to prostate-specific antigen (PSA) progression, and time to initiation of new antineoplastic therapy. Due to the differences in follow-up across the ARCHES and ARANOTE trials, a quantitative comparison of the safety profiles of the two treatments was not possible.
Study outcomes
The results from the MAIC analysis were presented at the 40th Annual European Association of Urology on 22 March 2025 and subsequently published in full in Future Oncology on 14 July 2025.[3][4]
The study outcomes showed that the primary endpoint of radiographic progression-free survival was significantly prolonged with enzalutamide compared to darolutamide (HR [95% confidence interval, CI]: 0.54 [0.32–0.93], p=0.03), equivalent to a 46% lower risk of radiographic progression or death with enzalutamide treatment. A 43% lower risk of progression to castration resistance (HR [95% CI]: 0.57 [0.34–0.94], p=0.03) was also seen with enzalutamide treatment compared to darolutamide. The rate of discontinuation due to adverse events (AEs) was comparable between patients receiving enzalutamide + ADT (7.2%) and patients receiving darolutamide + ADT (6.1%).[1][3][4]
The MAIC analysis published in Future Oncology adds to the comprehensive body of enzalutamide research, advancing clinician’s understanding on the effective management of mHSPC. Enzalutamide is currently approved in more than 80 countries worldwide, including in the United States, European Union and Japan. Since its initial approval in 2012, over 1.5 million patients have been treated with enzalutamide globally.[5]
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Clinical trials
A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES) – ClinicalTrials.gov ID NCT02677896
Darolutamide in Addition to ADT Versus ADT in Metastatic Hormone-sensitive Prostate Cancer (ARANOTE) – ClinicalTrials.gov ID NCT04736199
Highlights of prescribing information
Enzalutamide (Xtandi™; Astellas Pharma and Pfizer) [Prescribing Information]
Darolutamide (Nubeqa®; Bayer)[Prescribing Information]
Reference
[1] Armstrong AJ, Pandya BJ, Bhadauria HS, Ganguli A, Daki V, Moura A, Azad AA. Matching-adjusted indirect comparison of enzalutamide versus darolutamide doublet in mHSPC. Future Oncol. 2025 Jul 14:1-11. doi: 10.1080/14796694.2025.2526324. Epub ahead of print. PMID: 40654300.
[2] National Comprehensive Cancer Network (NCCN) Guidelines. Version 2. 2025. Online Last accessed in July 2025.
[3] European Association of Urology. EAU – EANM – ESTRO – ESUR – ISUP – SIOG Guidelines on Prostate Cancer 2024. Online. Last accessed in July 2025.
[4] Azad A, et al. P181: Matching-Adjusted Indirect Comparison (MAIC) between Enzalutamide (ENZA) and Darolutamide (DARO) doublet therapy for metastatic Hormone-sensitive Prostate Cancer (mHSPC). Presented at the 40th Annual European Association of Urology Congress (21-24 March 2025). Online. Last accessed in July 2025.
[5] Astellas. Data on File. XTANDI patient. June 2025.
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