Publications

Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC)

Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC)

Background: Clinically relevant outcomes in nmCRPC treated with androgen receptor-axis-targeted therapies (ARAT) may be inferior in patients with tumors harboring mutations bypassing androgen receptor signalling. This final update of a retrospective, multicenter analysis explores the association between genomic mutations in the PI3K-AKT and DDR signalling pathways with ARAT treatment outcomes in nmCRPC patients. Methods: Relevant clinical endpoint were collected for high-risk nmCRPC patients treated with an ARAT at APCaRI affiliated cancer centers, including median metastasis-free survival (MFS), overall survival (OS), PSA decline ≥ 50% (PSA50), and second progression free survival (PFS2). Archival tumor tissue was accessed for next generation gene sequencing, examining for genomic alterations in 500 genes, including those involved in the DDR and the PI3K-AKT signalling pathways. Comparison of outcomes of patients with DDR and PI3K-AKT pathway mutations was conducted using Cox proportional hazards regression using wildtype cases as the reference group, adjusting for PSA doubling time and pelvic lymphadenopathy. Results: Of the 37 patients included, 30 (82%) received apalutamide, 5 (13%) received darolutamide, and 2 (6%) received enzalutamide. 10 patients (27%) had PI3K-AKT pathway mutations (4 PTEN, 3 PIK3Ca, 2 PIK3C2G, 1 PIK3C2b), 8 patients (22%) had DDR gene mutations (3 ATM, 2 CHEK1, 1 BRCA2, 1 CDK12, 1 CHEK2, 1 FANCD2, 1 FANCL), and 1 patient (3%) had 2 MLH1 mutations (microsatellite instability). Of those who had subsequent treatment, 1 received enzalutamide and 5 received abiraterone. Patients with PI3K-AKT pathway mutations had significantly shorter MFS (4.8 mo; HR 4.2; 95% CI 1.2 – 15.0; p = 0.025). Those with DDR mutations had a trend towards shorter MFS (23.3 mo HR 3.7; 95% CI 0.71 – 13.4; p = 0.134). OS data remains immature. 4 (11%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations. Conclusions: This final analysis demonstrates that nmCRPC with PI3K and DDR signalling pathway mutations have poor clinical outcomes when treated with ARAT, likely secondary to decreased reliance on the androgen receptor signalling pathway. These results highlight the potential value of exploring targeted therapies, such as PARP or AKT inhibitors in patients with these mutations.

© 2022 by American Society of Clinical Oncology

Research Sponsor:

Bayer Canada, Jansen Canada.
Cite:
Richard GagnonSoufiane El HallaniRichard M. Lee-YingMichael Paul KolinskyDaniel Joseph KhalafSarah CookCatalina VasquezDivya SamuelJohn D LewisRehan FaridiMinal BorkarDaniel Yick Chin HengNimira S. AlimohamedJoseph D. RuetherGeoffrey GottoAdrian S. FaireyTarek A. Bismar, and Steven Yip

Journal of Clinical Oncology 2022 40:6_suppl175-175

Clinical Validation Trial of ClarityDX Prostate, a made-in-Alberta blood test to improve the diagnosis of Prostate Cancer

John Lewis will be presenting a seminar entitled “Clinical Validation Trial of ClarityDX Prostate, a made-in-Alberta blood test to improve the diagnosis of Prostate Cancer” at the University of Alberta Urology Grand Rounds this Friday, Feb 8, at the NAUC Auditorium. Please come out and join us for this early morning seminar, your presence is appreciated!
John will discuss the progress in the discovery and clinical validation of novel biomarkers for prostate cancer detection and prognosis. He will also give an overview of the Alberta Prostate Cancer Registry and Biorepository recruitment and future plans, and an overview and goals of the upcoming ClarityDX Prostate blood test clinical validation trial.
Date: Friday, February 8, 2019
Time: 7:00 am – 8:00 am
Location: NAUC Auditorium (7th floor) in the Kaye Edmonton Clinic
See you on Friday!

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