Androgen Synthesis Inhibitors vs Androgen Receptor Inhibitors and Survival in Metastatic Hormone-Sensitive Prostate Cancer.
8 affiliations
- 1Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City.
- 2Cancer Biostatistics, Huntsman Cancer Institute, University of Utah, Salt Lake City.
- 3Department of Medical Oncology, IRCCS San Raffaele Hospital, Comprehensive Cancer Center, Milan, Italy.
- 4Vita-Salute San Raffaele University, Milan, Italy.
- 5Division of Hematology and Oncology, Department of Internal Medicine, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
- 6Division of Medical Oncology, University of Kansas Cancer Center, Kansas City.
- 7Cardio-Oncology Program, Medical College of Georgia at Augusta University, Augusta.
- 8Mayo Clinic, Phoenix, Arizona.
Abstract
Importance
In metastatic hormone-sensitive prostate cancer (mHSPC), randomized clinical trials directly comparing androgen deprivation therapy intensification using androgen synthesis inhibitors (ASIs) vs next-generation androgen receptor inhibitors (ARIs) are lacking.Objective
To compare the outcomes associated with ASI vs ARI intensification therapy among patients with mHSPC in community or academic clinical practices.Design, setting, and participants
This was a retrospective cohort study of patients diagnosed with mHSPC between February 4, 2013, and April 29, 2024, with follow-up through the July 2024 data cut, providing a median (IQR) follow-up of 25.6 (24.5-26.6) months. Patient-level data were extracted from the nationwide US-based Flatiron Health electronic health record-derived deidentified research database of community and academic practices. Patients with evidence of an mHSPC diagnosis initiating treatment with an ASI (abiraterone acetate) or ARI (apalutamide or enzalutamide) within 3 months prior to or 6 months after an mHSPC diagnosis were eligible. Patients with prior docetaxel receipt were excluded.Exposure
Treatment with an ASI vs an ARI.Main outcomes and measures
The primary outcome was overall survival (OS), defined as time in months from mHSPC diagnosis to death or censoring at last recorded activity.Results
Of 3404 patients (median [IQR] age, 73 [66-80] years), 1830 received treatment with an ASI (abiraterone), and 1574 with an ARI (507 apalutamide, 1067 enzalutamide). Following inverse probability of treatment weighting, patients receiving an ARI had significantly longer OS (median, 67.9 months [95% CI, 67.5 months to not reached]) compared with patients treated with the ASI (median, 57.2 months [95% CI, 52.7-63.3 months]) (hazard ratio [HR], 0.74 [95% CI, 0.64-0.87]); P < .001). Results were similar in sensitivity analyses using therapy initiation as the index date (HR, 0.73 [95% CI, 0.62-0.84]; P < .001) and when restricted to index dates on or after December 16, 2019 (HR, 0.67 [95% CI, 0.56-0.81]; P < .001). The association was not modified by insurance status or socioeconomic status.Conclusions and relevance
In this cohort study of 3404 patients with mHSPC, treatment intensification with an ARI was associated with significantly longer OS compared with an ASI. These findings may help guide clinical treatment selection and patient counseling. However, given conflicting clinical practice data across differing database populations, only a randomized clinical trial can definitively answer this question.
Related
- Clinical and genomic determinants of extraordinary response and resistance to androgen receptor pathway inhibitors in men with metastatic androgen pathway modulator sensitive (APMS) prostate cancer
- Exceptional long-term responses in metastatic androgen pathway-modulation sensitive prostate cancer
- Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence
- Trial-reported arthralgia of androgen deprivation therapy plus androgen receptor signaling inhibitors in prostate cancer: evidence from phase III randomized trials
- ERG inhibition selectively sensitizes ERG-positive prostate cancer to radiation through DNA repair vulnerabilities and enhances response to androgen receptor inhibitors.
BibTeX
@article{gebrael2026androgen,
title = {{Androgen Synthesis Inhibitors vs Androgen Receptor Inhibitors and Survival in Metastatic Hormone-Sensitive Prostate Cancer.}},
author = {Georges Gebrael and Yeonjung Jo and Varun Nandakumar and Zeynep Irem Ozay and Chiara Mercinelli and Gabriel Hooper and Micah Ostrowski and Nicolas Sayegh and Edwin Lin and Krishnam Goel and Haoran Li and Vinay Mathew Thomas and Sumati Gupta and Avirup Guha and Irbaz Bin Riaz and Neeraj Agarwal and Umang Swami},
journal = {JAMA network open},
year = {2026},
month = oct,
doi = {10.1001/jamanetworkopen.2026.39458},
url = {https://europepmc.org/article/MED/42900475},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Androgen Synthesis Inhibitors vs Androgen Receptor Inhibitors and Survival in Metastatic Hormone-Sensitive Prostate Cancer.
AU - Georges Gebrael
AU - Yeonjung Jo
AU - Varun Nandakumar
AU - Zeynep Irem Ozay
AU - Chiara Mercinelli
AU - Gabriel Hooper
AU - Micah Ostrowski
AU - Nicolas Sayegh
AU - Edwin Lin
AU - Krishnam Goel
AU - Haoran Li
AU - Vinay Mathew Thomas
AU - Sumati Gupta
AU - Avirup Guha
AU - Irbaz Bin Riaz
AU - Neeraj Agarwal
AU - Umang Swami
PY - 2026
DA - 2026/10/01
JO - JAMA network open
DO - 10.1001/jamanetworkopen.2026.39458
UR - https://europepmc.org/article/MED/42900475
AB - Importance In metastatic hormone-sensitive prostate cancer (mHSPC), randomized clinical trials directly comparing androgen deprivation therapy intensification using androgen synthesis inhibitors (ASIs) vs next-generation androgen receptor inhibitors (ARIs) are lacking.Objective To compare the outcomes associated with ASI vs ARI intensification therapy among patients with mHSPC in community or academic clinical practices.Design, setting, and participants This was a retrospective cohort study of patients diagnosed with mHSPC between February 4, 2013, and April 29, 2024, with follow-up through the July 2024 data cut, providing a median (IQR) follow-up of 25.6 (24.5-26.6) months. Patient-level data were extracted from the nationwide US-based Flatiron Health electronic health record-derived deidentified research database of community and academic practices. Patients with evidence of an mHSPC diagnosis initiating treatment with an ASI (abiraterone acetate) or ARI (apalutamide or enzalutamide) within 3 months prior to or 6 months after an mHSPC diagnosis were eligible. Patients with prior docetaxel receipt were excluded.Exposure Treatment with an ASI vs an ARI.Main outcomes and measures The primary outcome was overall survival (OS), defined as time in months from mHSPC diagnosis to death or censoring at last recorded activity.Results Of 3404 patients (median [IQR] age, 73 [66-80] years), 1830 received treatment with an ASI (abiraterone), and 1574 with an ARI (507 apalutamide, 1067 enzalutamide). Following inverse probability of treatment weighting, patients receiving an ARI had significantly longer OS (median, 67.9 months [95% CI, 67.5 months to not reached]) compared with patients treated with the ASI (median, 57.2 months [95% CI, 52.7-63.3 months]) (hazard ratio [HR], 0.74 [95% CI, 0.64-0.87]); P < .001). Results were similar in sensitivity analyses using therapy initiation as the index date (HR, 0.73 [95% CI, 0.62-0.84]; P < .001) and when restricted to index dates on or after December 16, 2019 (HR, 0.67 [95% CI, 0.56-0.81]; P < .001). The association was not modified by insurance status or socioeconomic status.Conclusions and relevance In this cohort study of 3404 patients with mHSPC, treatment intensification with an ARI was associated with significantly longer OS compared with an ASI. These findings may help guide clinical treatment selection and patient counseling. However, given conflicting clinical practice data across differing database populations, only a randomized clinical trial can definitively answer this question.
SN - 2574-3805
ER -