Modeled Early Longitudinal PSA Kinetics Prognostic Value in Rising PSA Prostate Cancer Patients after Local Therapy Treated with ADT +/− Docetaxel

SIMPLE SUMMARY: In prostate cancer patients with rising prostate-specific antigens (PSAs) after primary local therapy, and at high risk of metastatic disease based on a high Gleason score or ISUP grades 4–5 and/or short PSA doubling time, androgen-deprivation therapy (ADT) was shown to be effective with or without salvage radiotherapy. In the present paper, the analysis of a phase III trial dataset comparing ADT +/− docetaxel demonstrates that longitudinal PSA kinetics during the first 100 days of treatment, assessed using mathematical modeling, is associated with patient prognosis. Indeed, multivariate analyses showed that the modeled PSA production rate constant KPROD, and the elimination rate constant KELIM, exhibited strong and independent prognostic values regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), respectively. As it was shown with the longitudinal CA-125 kinetic in ovarian cancers, the modeled longitudinal PSA kinetics during the 100 days of treatment may represent a novel prognostic factor in patients with metastatic prostate cancers. ABSTRACT: Background: In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values. Methods: Phase III clinical trial dataset (NCT00764166) comparing ADT +/− docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses. Results: Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time. Conclusion: In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.