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.
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

Enbridge Ride to Conquer Cancer 2018

APCaRI members participated in the Enbridge Ride to Conquer Cancer, benefiting the Alberta Cancer Foundation, again this year! The ride is a 2-day cycling adventure that covers 200 km along the majestic Rockies. Unfortunately,  the air was so smoky from fires that the air quality health index reached 10+.  The 1800 riders rode approximately 75 km, but had to stop due to potential negative health risks from the smoke.
Although the ride was shortened it was still an amazing experience for the APCaRI member-riders and the Cross Cancer riding team. Thank you again to the amazing team of volunteers that helped to organize, set-up and transport riders to Calgary!
Most importantly, over $8 M dollars was raised to support cutting-edge cancer research in Alberta! We are very thankful for the support we received, which will help us to beat prostate cancer.
If you didn’t get a chance to support one of our riders, please consider contributing to the team’s efforts at our DONATE page

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