A real-world clinicogenomic study of androgen receptor mutations and co-mutations in prostate cancer: Clinical implications.
Authors: Sturgill Emma G. , Luckett Daniel J. , Agrawal Tarun , Best Jordan T. , Williams Rikki N. , Bupathi Manojkumar , Fleming Mark T. , Schnadig Ian D. , Subbiah Vivek , Spigel David R. , Burris Howard A. , McKenzie Andrew Jacob , Garmezy Benjamin 
Published: February 2025

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Background:
While most prostate cancer (PCa) patients (pts) initially respond to androgen deprivation therapy, resistance commonly develops, resulting in castration-resistant PCa. In certain patients, androgen receptor (
AR
) mutations permit tumor cells to proliferate despite the absence of circulating androgens. This study leverages real-world clinicogenomic data to investigate the prevalence and clinical implications of
AR
mutations and co-mutations.
Methods:
We analyzed 3,753 pt records with PCa who underwent next-generation sequencing (NGS) from January 1, 2014 to October 1, 2024. NGS was ordered by >400 physicians from >180 community-based oncology clinics across the Sarah Cannon Research Institute network, and results were collated with pt medical records in the software platform, Genospace. Pts were stratified into
AR
-mutated (
AR
m; 306 pts),
AR
-amplified (
AR
amp; 231 pts), and
AR
wild-type (
AR
WT; 3,216 pts) cohorts. Pts with multiple primary cancers were excluded.
Results:
AR
mutations were detected in 306 pts (8%), with a higher detection rate in plasma-
versus
tissue-based NGS (15% vs 2%; p<0.01).
AR
mutations were more common in older pts, with 68% of
AR
m pts >70 years old compared to 53% of
AR
WT pts (p<0.01). The most common
AR
mutations included L702H (51%, 156 pts), T878A (38%, 115 pts), H875Y (23%, 70 pts) and W742C (8%, 25 pts), and over half of
AR
m pts reported multiple
AR
mutations (51%, 156 pts). Several genes were more frequently mutated in
AR
m
versus
AR
WT pts, including
TP53
(43% vs 32%),
PTEN
(10% vs 6%),
BRCA2
(9% vs 4%),
RB1
(5% vs 2%), and
BRCA1
(4% vs 1%; p<0.01 for all).
AR
m pts reported a higher frequency of microsatellite instability (MSI) compared to
AR
WT pts (11% vs 2%; p<0.01). Within the
AR
m cohort, MSI was more frequently detected by tissue-
versus
plasma-based NGS (26% vs 7%; p<0.01). Specific
AR
mutations were enriched in MSI
versus
microsatellite stable (MSS) pts, including H875Y (50% vs 20%) and V716M (31% vs 2%; p<0.01 for both). Additionally,
BRCA1/2
mutations were more common in
AR
m/MSI pts
versus
AR
m/MSS pts (
BRCA1
: 15% vs 3%;
BRCA2
: 35% vs 6%; p<0.01 for both). Pts in both the
AR
m (3.3 yrs) and
AR
amp (2.1 yrs) cohorts exhibited shorter overall survival from metastatic staging compared to the
AR
WT cohort (9.0 yrs; p<0.01 for both). Neither specific
AR
mutations nor MSI status correlated with survival outcomes.
Conclusions:
AR
mutations are frequently detected by plasma-based NGS in the real-world setting, possibly due to test selection at disease progression and/or sampling of tumor heterogeneity. However, plasma-based NGS may miss other critical alterations, such as MSI status. The high co-occurrence of MSI in
AR
-mutated PCa suggests potential for combination therapies involving immunotherapy and novel AR degraders. These findings emphasize the need for tissue- and plasma-based genomic profiling to guide therapeutic decisions and optimize treatment strategies for advanced PCa.