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Updated: Jul 2, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration
Zeynep B Zengin1, Nicholas C Henderson2, Joseph J Park3
1Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Background:
AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear.
Methods:
Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types.
Results:
In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%).
Conclusion:
In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.
Insights
Androgen receptor (AR) gene alterations can emerge during prostate cancer treatment. AR amplifications were linked to a longer time to progression in patients receiving androgen receptor targeting agents (ARTA).
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Androgen receptor (AR) gene alterations can develop under selective pressure from testosterone suppression and androgen receptor targeting agents (ARTA).
- The clinical significance of these AR alterations concerning ARTA treatment efficacy and patient outcomes remains largely undetermined.
Purpose of the Study:
- To investigate the development of AR alterations in castration-resistant prostate cancer (CRPC).
- To evaluate the association between AR alterations and clinical outcomes in patients treated with ARTA.
Main Methods:
- A retrospective analysis of 540 CRPC patients from the PROMISE database who received ARTA and underwent genomic testing.
- Stratification of patients based on the timing of genomic testing (pre- or post-ARTA treatment).
- Comparison of clinical outcomes, including time to progression and PSA response, based on AR alteration status.
Main Results:
- AR amplifications were associated with a significantly longer time to progression (25.7 months) compared to patients without AR alterations (9.6 months; p=0.03) in the pre-ARTA group.
- In the post-ARTA group, AR mutations and amplifications were detected in 18.5% and 35.7% of patients, respectively.
- The L702H mutation was the most frequent AR mutation in the post-ARTA cohort (9.9%).
Conclusions:
- AR amplifications correlate with extended time to progression during initial ARTA therapy for CRPC.
- This study highlights the importance of AR alterations in predicting treatment response.
- Further prospective research is warranted to refine therapeutic strategies for patients with specific AR alterations.
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