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

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

doi:10.21203/rs.3.rs-3201150/v1

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

Res Sq [Preprint]. 2023 Aug 10:rs.3.rs-3201150. doi: 10.21203/rs.3.rs-3201150/v1.

Authors

Tanya Dorff¹, Zeynep Zengin¹, Nicholas Henderson², Alicia Ali³, Charles Nguyen⁴, Clara Hwang⁴, Pedro C Barata⁵, Mehmet Bilen⁶, Laura Graham⁶, George Mo⁷, Deepak Kilari⁷, Abhishek Tripathi⁸, Matthew Labriola⁸, Shoshana Rothstein⁸, Rohan Garje⁸, Vadim Koshkin⁹, Vaibhav Patel¹⁰, Michael Schweizer¹¹, Andrew Armstrong¹², Rana McKay¹³, Ajjai Alva¹⁴

Affiliations

¹ City of Hope.
² Joseph Park.
³ University of Michigan Medical School.
⁴ Henry Ford Health System.
⁵ Division of Medical Oncology, Department of Medicine, University Hospitals Seidman Cancer Center and Case Comprehensive Cancer Center.
⁶ University of Colorado Anschutz Cancer Center.
⁷ Medical College of Wisconsin.
⁸ university of Iowa.
⁹ University of California San Francisco.
¹⁰ Icahn School of Medicine at Mount Sinai.
¹¹ University of Washington.
¹² Duke University Medical Center.
¹³ Moores Cancer Center.
¹⁴ University of Michigan-Ann Arbor.

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: To our knowledge, this is the largest real-world clinicogenomics database-driven study exploring the development of ARalterations 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.

Keywords: Prostate cancer; androgen receptor; genomic testing.

Publication types

Preprint

Abstract

Publication types

Grants and funding