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Comparative Study
. 2025 Jul;42(7):3437-3454.
doi: 10.1007/s12325-025-03207-6. Epub 2025 May 29.

Overall Survival with Apalutamide Versus Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer

Mehmet A Bilen  1 , Benjamin Lowentritt  2 , Ibrahim Khilfeh  3 , Carmine Rossi  4 , Shawn Du  3 , Frederic Kinkead  4 , Lilian Diaz  4 , Dominic Pilon  4 , Lorie Ellis  3 , Neal D Shore  5
Affiliations
Comparative Study

Overall Survival with Apalutamide Versus Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer

Mehmet A Bilen et al. Adv Ther. 2025 Jul.

Abstract

Introduction: Survival outcomes associated with different androgen receptor pathway inhibitors (ARPIs) prescribed for the treatment of metastatic castration (hormone)-sensitive prostate cancer (mCSPC) have not been directly compared. The objective of this study was to compare overall survival (OS) by 24 months among ARPI-naïve patients with mCSPC initiating apalutamide or enzalutamide.

Methods: A retrospective, causal longitudinal inverse probability of treatment weighted analysis was conducted to compare OS between patients initiating apalutamide or enzalutamide between December 2019 and December 2023 using de-identified linked US clinical and insurance claims data. Patients were excluded if they had prior exposure to ARPIs, had evidence of castration resistance, had < 12 months of database activity prior to ARPI initiation, were diagnosed with other primary cancers, or were treated with other advanced prostate cancer (PC)-related treatment (except docetaxel). Using an intention-to-treat approach, weighted Cox proportional hazards models were used to compare OS by 24 months between patients treated with apalutamide or enzalutamide (primary analyses; exploratory analyses used all available follow-up).

Results: Overall, 1810 and 1909 ARPI-naïve patients who initiated apalutamide or enzalutamide, respectively, were included. Measured baseline characteristics between cohorts were well balanced after weighting (for both: mean age 73.0 years, ~ 60% white, ~ 23% black or African American, ~ 78% Medicare-insured, mean Quan-CCI 8.6, ~ 20% with visceral metastasis, 56.2% with de novo PC). At 24 months post index, there was a statistically significant 23% reduction in the risk of mortality among patients who initiated apalutamide compared with enzalutamide (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.62, 0.96; p = 0.019). Results remained consistent when using all available follow-up metrics (HR 0.77; 95% CI 0.64, 0.93; nominal p = 0.008).

Conclusion: In this head-to-head causal analysis among ARPI-naïve patients with mCSPC, treatment with apalutamide resulted in better survival outcomes at 24 months compared with enzalutamide. Longer follow-up studies are required to fully determine the therapeutic comparator impact of these agents.

Keywords: Androgen receptor pathway inhibitors; Comparative effectiveness; Hormonal antineoplastic agents; Hormone-sensitive; Prostatic neoplasms.

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Conflict of interest statement

Declarations. Conflict of Interest: Mehmet A. Bilen has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Johnson & Johnson, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed outside of the current study. Benjamin Lowentritt is an employee of Chesapeake Urology and has received consulting fees from Johnson & Johnson, Dendreon, Astellas Pharma, Bayer, AstraZeneca/MedImmune, Merck, Tolmar, Abbvie, Pfizer, and Myovant Sciences. Ibrahim Khilfeh and, Shawn Du are employees and stockholders of Johnson & Johnson. Lorie Ellis was an employee of Johnson & Johnson at the time the study was conducted. Carmine Rossi, Frederic Kinkead, Lilian Diaz, and Dominic Pilon are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Johnson & Johnson. Neal D. Shore is an employee of the Carolina Urologic Research Center and has received consulting fees from Johnson & Johnson, Bayer, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Astellas Pharma, AbbVie, Merck, Bristol Myers Squibb/Sanofi, Exact Imaging, FerGene, InVitae, MDxHealth, Myriad Genetics, Propella Therapeutics, Genzyme, Sanofi, CG Oncology, Genesis Cancer Care, Urogen pharma, Speciality Networks, PeerView, Clarity Pharmaceuticals, Lantheus Medical Imaging, Lilly, Photocure, Telix Pharmaceuticals, AIkido Pharma, Arquer Diagnostics, Asieris Pharmaceuticals, Minomic, Novartis, PlatformQ Health, Promaxo, Protara Therapeutics, Fize Medical, Accord Research, Antev, Aura Biosciences, Bioprotect, and Sumitomo Pharma Oncology. NS has received research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Boston Scientific, Clovis Oncology, Dendreon, Exact Imaging, Ferring, Foundation Medicine, InVitae, Johnson & Johnson, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Sanofi, Sesen Bio, Tolmar, CG Oncology, DisperSol, FORMA Therapeutics, Guardant Health, Jiangsu Yahong Meditech, Novartis, Pacific Edge, POINT Biopharma, Propella Therapeutics, SeaGen, MT Group, Theralase, Veru, Zenflow, Advantagene, Aragon Pharmaceuticals, Endocyte, Exelixis, FKD Therapies, Genentech, Istari Oncology, Medivation, OncoCellMDx, ORIC Pharmaceuticals, Palette Life Sciences, Plexxikon, RhoVac, Steba Biotech, Urogen pharma, Urotronic, US Biotest, and Vaxiion for work performed outside of the current study. Ethical Approval: This study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments and considered exempt research under 45 CFR § 46.104(d)(4) as it involved only the secondary use of data that were de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA), specifically, 45 CFR § 164.514.

Figures

Fig. 1
Fig. 1
Sample selection. ARPI androgen receptor pathway inhibitor, mCSPC metastatic castration-sensitive prostate cancer, PARP poly(ADP-ribose) polymerase
Fig. 2
Fig. 2
Overall survival among patients initiating apalutamide versus enzalutamide. ADT androgen deprivation therapy, CI confidence interval, HR hazard ratio, PC prostate cancer. *Significant at the 5% level. aPropensity scores were generated using probability estimates from a logistic regression models using the following predictors: age (continuous), race, geographic region, payer, year of index date, time between metastasis and index date (continuous and categorical), time between PC diagnosis and index date (continuous), de novo PC, ADT use overlapping with index date, first-generation antiandrogen use, chemotherapy use, types of metastases (bone, nodal, visceral, and metastasis in multiple sites), Quan-Charlson Comorbidity Index (continuous), most recent prostate-specific antigen level (categorical), and earliest Gleason score (categorical). Each patient was attributed an inverse probability of treatment weight that was defined as follows: 1/(propensity score) for the apalutamide cohort and 1/(1 − propensity score) for the enzalutamide cohort. Normalized inverse probability of treatment weights were truncated at the 95th percentiles. bHR < 1 indicates that the apalutamide cohort had a lower rate of death compared to the enzalutamide cohort
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References

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