Abstract 583P
Background
Baseline high ptDNA fraction and androgen receptor (AR) copy number (CN) gain identify mCRPC patients (pts) with worse outcomes on abiraterone (abi) or enzalutamide (enza). This study aimed to assess if plasma DNA analysis associates with PSA kinetics.
Methods
In a prospective biomarker study, targeted next generation sequencing and digital droplet PCR were performed to evaluate ptDNA fraction and AR CN from plasma samples. We divided pts into two groups: high and low according to median ptDNA level and in AR gain and normal according to AR CN cutoff of 1.92. We explored PSA response endpoints and their correlation with ptDNA and AR status and progression free/overall survival (PFS/OS).
Results
From April 2013 to December 2018, 220 baseline samples were collected from mCRPC treated with abi (n=140) or enza (n=80). A lower rate of PSA decline ≥50% was observed in pts with high ptDNA and AR gain (p=0.012 and p=0.0003, respectively). A faster time to PSA nadir was reported in pts with high baseline ptDNA and AR gain compared to low ptDNA and AR normal [1.8 vs 3.7 months (mo), p=0.012, and 1.8 vs 3.0 mo, p=0.0002, respectively]. A meaningful shorter PSA doubling time (DT) from nadir was shown in men with high vs low ptDNA and AR gain vs normal (2.5 vs 3.8 mo, p=0.024, and 2.4 vs 3.6 mo, p=0.001, respectively) as well as a significant higher PSA DT velocity from nadir (14.3 vs 3.3 mo, p=0.0002, and 27.8 vs 2.8 mo, p<0.0001, respectively). Combining ptDNA fraction and AR CN, we found a different PSA-PFS among four groups: 1) low ptDNA/AR normal, 2) high ptDNA/AR normal, 3) low ptDNA/AR gain, and 4) high ptDNA/AR gain (11.4 vs 5 vs 4.8 vs 3.7 mo, p<0.0001). In addition, there were similar results among these four cohorts for radiographic-PFS and OS. In a multivariable analysis, high ptDNA, AR gain, PSA DT and PSA DT velocity remained independent predictors of PSA-PFS (HR 1.92, 95% CI 1.27-2.9, p=0.002, HR 1.66, 95% CI 1.02-2.7, p=0.04, HR 0.91 96% CI 0.85-0.97, p=0.004, and HR 1.0 95% CI 1.01-1.02, p=0.003, respectively).
Conclusions
Elevated ptDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abi or enza. Further studies to validate these findings are warranted.
Clinical trial identification
Prospective biomarker study (REC 2192/2013).
Editorial acknowledgement
Legal entity responsible for the study
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy.
Funding
Has not received any funding.
Disclosure
V. Conteduca: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal and Institutional, Sponsor/Funding: Bayer; Financial Interests, Personal, Other, travel support: Sanofi; Financial Interests, Personal, Other, travel support: Ipsen. G. Attard: Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Arno Therapeutics; Financial Interests, Personal and Institutional, Research Grant: Innocrin Pharma; Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: Sanofi-Aventis; Financial Interests, Personal, Advisory Board: Roche/Ventana; Financial Interests, Personal, Advisory Board, Travel support: Pfizer; Financial Interests, Personal, Advisory Board, Travel support: Abbott Laboratories; Financial Interests, Personal, Advisory Board, Travel support: Bayer Healthcare; Financial Interests, Personal, Advisory Board, Travel support: Essa Pharmaceuticals; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Veridex; Financial Interests, Personal, Advisory Board: Millennium Pharma. U. De Giorgi: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Sanofi; Financial Interests, Personal, Advisory Board: Janssen-Cilag; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Pharmamar. All other authors have declared no conflicts of interest.