Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration

Zeynep B Zengin; Nicholas C Henderson; Joseph J Park; Alicia Ali; Charles Nguyen; Clara Hwang; Pedro C Barata; Mehmet A Bilen; Laura Graham; George Mo; Deepak Kilari; Abhishek Tripathi; Matthew Labriola; Shoshana Rothstein; Rohan Garje; Vadim S Koshkin; Vaibhav G Patel; Michael T Schweizer; Andrew J Armstrong; Rana R McKay; Ajjai Alva; Tanya Dorff

doi:10.1038/s41391-024-00805-3

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration

Prostate Cancer Prostatic Dis. 2024 Feb 22. doi: 10.1038/s41391-024-00805-3. Online ahead of print.

Authors

Zeynep B Zengin¹, Nicholas C Henderson², Joseph J Park³, Alicia Ali³, Charles Nguyen³, Clara Hwang⁴, Pedro C Barata⁵, Mehmet A Bilen⁶, Laura Graham⁷, George Mo⁸, Deepak Kilari⁹, Abhishek Tripathi¹⁰, Matthew Labriola¹¹, Shoshana Rothstein¹², Rohan Garje¹³, Vadim S Koshkin¹⁴, Vaibhav G Patel^{15

16}, Michael T Schweizer⁸, Andrew J Armstrong¹¹, Rana R McKay¹⁷, Ajjai Alva³, Tanya Dorff¹⁸

Affiliations

¹ Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
² Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
³ Division of Hematology and Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵ Tulane Cancer Center, Tulane University, New Orleans, LA, USA.
⁶ Winship Cancer Institute of Emory University, Atlanta, GA, USA.
⁷ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ University of Washington/Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹ Department of Medicine, Froedtert Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁰ Stephenson Cancer Center, Oklahoma City, OK, USA.
¹¹ Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA.
¹² Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
¹³ Holden Comprehensive Cancer Center, Iowa City, IA, USA.
¹⁴ Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Arvinas Inc, New Haven, CT, USA.
¹⁷ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁸ Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. tdorff@coh.org.

PMID: 38383885
DOI: 10.1038/s41391-024-00805-3

Abstract

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.