Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)

Abstract

Background: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment.

Objective: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy.

Design, setting, and participants: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Patients received docetaxel (75mg/m²) or cabazitaxel (20 or 25mg/m²) as first-line chemotherapy (FIRSTANA), and cabazitaxel (20 or 25mg/m²) as second-line chemotherapy (PROSELICA).

Outcome measurements and statistical analysis: Associations between cfDNA concentration and prostate-specific antigen (PSA) response were tested using logistic regression models. Survival was estimated using Kaplan-Meier methods for cfDNA concentration grouped by quartile. Cox proportional hazard models, within each study, tested for associations with radiological progression-free survival (rPFS) and overall survival (OS), with multivariable analyses adjusting for baseline prognostic variables. Two-stage individual patient meta-analysis combined results for cfDNA concentrations for both studies.

Results and limitations: In 2502 samples, baseline log₁₀ cfDNA concentration correlated with known prognostic factors, shorter rPFS (hazard ratio [HR]=1.54; 95% confidence interval [CI]: 1.15-2.08; p=0.004), and shorter OS on taxane therapy (HR=1.53; 95% CI: 1.18-1.97; p=0.001). In multivariable analyses, baseline cfDNA concentration was an independent prognostic variable for rPFS and OS in both first- and second-line chemotherapy settings. Patients with a PSA response experienced a decline in log₁₀ cfDNA concentrations during the first four cycles of treatment (per cycle -0.03; 95% CI: -0.044 to -0.009; p=0.003). Study limitations included the fact that blood sample collection was not mandated for all patients and the inability to specifically quantitate tumour-derived cfDNA fraction in cfDNA.

Conclusions: We report that changes in cfDNA concentrations correlate with both rPFS and OS in patients receiving first- and second-line taxane therapy, and may serve as independent prognostic biomarkers of response to taxanes.

Patient summary: In the past decade, several new therapies have been introduced for men diagnosed with metastatic prostate cancer. Although metastatic prostate cancer remains incurable, these novel agents have extended patient survival and improved their quality of life in comparison with the last decade. To further optimise treatment allocation and individualise patient care, better tests (biomarkers) are needed to guide the delivery of improved and more precise care. In this report, we assessed cfDNA in over 2500 blood samples from men with prostate cancer who were recruited to two separate international studies and received taxane chemotherapy. We quantified the concentration of cfDNA fragments in blood plasma, which partly originates from tumour. We identified that higher concentrations of circulating cfDNA fragments, prior to starting taxane chemotherapy, can be used to identify patients with aggressive prostate cancer. A decline in cfDNA concentration during the first 3-9 wk after initiation of taxane therapy was seen in patients deriving benefit from taxane chemotherapy. These results identified circulating cfDNA as a new biomarker of aggressive disease in metastatic prostate cancer and imply that the study of cfDNA has clinical utility, supporting further efforts to develop blood-based tests on this circulating tumour-derived DNA.

Keywords: Cabazitaxel; Circulating cell-free DNA; Docetaxel; FIRSTANA; PROSELICA; Taxane chemotherapy; cfDNA.

Fig. 1

Correlation and coefficient of variation (CV) between both baseline samples taken between 1 and 7 d apart. (A) Relationship between log₁₀-transformed cfDNA concentration (ng/ml) at screening and at C1 in 507 paired samples derived from n = 571 patients. Correlation coefficient = 0.84 (Pearson's rho) with p < 0.001. (B) CV of baseline samples depicted in a frequency chart with mean and median CV of 0.12 and 0.08 with 95% CI of 0.11 and 0.13, respectively. Mean CV is shown in solid line. C = cycle; cfDNA = cell-free DNA; CI = confidence interval; CV = coefficient of variation.

Fig. 2

Mean log₁₀ cfDNA concentrations and 95% confidence intervals per cycle by PSA response (decrease of 50% at any time). cfDNA = cell-free DNA; PSA = prostate-specific antigen.

Fig. 3

Correlation of baseline cfDNA concentration quartiles with rPFS and OS. (A) Kaplan-Meier curve of rPFS by baseline log₁₀ cfDNA concentration quartiles. (B) Forest plot for rPFS (multivariable analysis model) for baseline log₁₀ cfDNA concentration for each study and combined estimate. (C) Kaplan-Meier curve of OS by baseline cfDNA concentration quartiles. (D) Forest plot for OS (multivariable analysis model) for baseline log₁₀ cfDNA concentration for each study and combined estimate. The multivariable Cox model included baseline log₁₀ cfDNA concentration, ECOG PS at baseline (0 vs 1–2), visceral metastases, bone-only disease, Gleason score, baseline pain, baseline albumin, baseline ALP, baseline haemoglobin, baseline LDH, baseline NLR and baseline PSA. The I² test displays and tests the level of heterogeneity between the studies, which is nonsignificant for cfDNA. ALP = alkaline phosphatase; cfDNA = cell-free DNA; CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; HR, = hazard ratio; LDH = lactate dehydrogenase; NLR = Neutrophil-lymphocyte ratio; OS = overall survival; PSA = prostate-specific antigen; rPFS = radiological progression-free survival.