ASCO 2017: Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel in metastatic castration resistant prostate cancer

Chicago, IL ( Glutathione S-transferase (GSTP1) inactivation is associated with CpG island hypermethylation in > 90% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to Docetaxel (DTX) and overall survival (OS) in phase I/II mCRPC cohorts. Dr. Mahon presented data from a post hoc analysis of a phase III study aiming to test the association between circulating mGSTP1 DNA levels and outcomes after 2 cycles of docetaxel (PRECYC3). The secondary objective was to see if baseline mGSTP1 predicts overall survival. 

The phase III SYNERGY study tested DTX +/- custirsen as 1st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline and at PRECYC3 of DTX +/- custirsen from 600 patients enrolled on the SYNERGY study. mGSTP1 levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP), and OS. 

On interim analysis of 300 patients, serum mGSTP1 was detectable at baseline in 80% and at PRECYC3 in 44% of patients. Undetectable mGSTP1 levels after 2 cycles of DTX correlated with a ≥30% fall in PSA within 3m of starting DTX (p < 0.001). Detectable baseline and after two cycles of DTX mGSTP1 predicted shorter TTP after DTX (baseline; HR 1.6 95%CI 1.1-2.3; p = 0.01 and PRECYC3 HR 2.2 95%CI 1.6-2.9; p < 0.001). Detectable mGSTP1 at both time points predicted shorter OS (Baseline; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p < 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p < 0.001). In those with detectable baseline mGSTP1, 50% had undetectable PRECYC3 mGSTP1 predicting > 30% fall in PSA within 3m (p < 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p < 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p < 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable PRECYC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p < 0.001). Detectable mGSTP1 at both time points independently predicted OS (baseline; HR1.8 95% CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p < 0.001). 

Dr. Kate Mahon concluded by stating that this study validates circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX. It is more accurate than PSA and may be used as an early surrogate marker for therapeutic activity in clinical trials.

Presented By: Kate Lynette Mahon, Camperdown, Australia; Garvan Institute of Medical Research, Sydney, Australia

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA