Kate L Mahon1, Wenjia Qu2, Hui-Ming Lin3, Calan Spielman2, Daniel Cain4, Cindy Jacobs4, Martin R Stockler5, Celestia S Higano6, Johann S de Bono7, Kim N Chi8, Susan J Clark3, Lisa Glen Horvath9. 1. Chris O'Brien Lifehouse, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia; University of NSW, Sydney, Australia; University of Sydney, Sydney, Australia. 2. Garvan Institute of Medical Research, Sydney, Australia. 3. Garvan Institute of Medical Research, Sydney, Australia; University of NSW, Sydney, Australia. 4. Oncogenex Pharmaceuticals Inc., Bothell, WA, USA. 5. Chris O'Brien Lifehouse, Sydney, Australia; University of Sydney, Sydney, Australia; National Health and Medical Research Council Clinical Trials Centre, Sydney, Australia. 6. University of Washington, Fred Hutchinson Cancer Research Centre, Seattle, WA, USA. 7. Royal Marsden Hospital and Institute of Cancer Research, London, UK. 8. University of British Columbia, BC Cancer Agency, Vancouver Prostate Centre, Vancouver, BC, Canada. 9. Chris O'Brien Lifehouse, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia; University of NSW, Sydney, Australia; University of Sydney, Sydney, Australia. Electronic address: lisa.horvath@lh.org.au.
Abstract
BACKGROUND:Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.
RCT Entities:
BACKGROUND:Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.
Authors: Ciara Conduit; Blossom Mak; Wenjia Qu; Juliana Di Lulio; Ronan Burder; Matthias Bressel; Thomas Cusick; Haryana M Dhillon; Richard De Abreu Lourenço; Craig Underhill; Javier Torres; Megan Crumbaker; Florian Honeyball; Anthony Linton; Ray Allen; Ian D Davis; Susan J Clark; Lisa G Horvath; Kate L Mahon Journal: Ther Adv Med Oncol Date: 2022-04-18 Impact factor: 5.485
Authors: Romina Silva; Bruce Moran; Niamh M Russell; Ciara Fahey; Tatjana Vlajnic; Rustom P Manecksha; Stephen P Finn; Donal J Brennan; William M Gallagher; Antoinette S Perry Journal: Epigenetics Date: 2020-01-31 Impact factor: 4.528