Changing metastatic patterns associate with dynamics of circulating tumor DNA in metastatic castration-resistant prostate cancer

Abstract Background Circulating tumor DNA (ctDNA) acts as an early biomarker of the efficacy of androgen receptor signaling inhibitor (ARSI) therapy. In this study, we aimed to reveal if ctDNA can supplement imaging to better predict metastasis burden and radiographic progression disease (PD) in metastatic castration-resistant prostate cancer (mCRPC). Methods Targeted next-generation sequencing was performed to assess ctDNA fraction. Radiographic evidence was documented by conventional imaging according to Prostate Cancer Working Group 3 criteria. Results We prospectively collected plasma samples from 112 mCRPC with bone (n = 77), lymph nodal (n = 31), and visceral (n = 4) metastases. Only bone metastatic patterns were significantly associated with median ctDNA at baseline, during treatment and at PD (P <.0001). At first radiographic restaging, 24 (31.2%) men with a progressive worsening of bone disease had early ctDNA rise with a % ctDNA variation of 150.6% (interquartile range [IQR] = 104.9-210.7] compared with 11.1% (IQR = 0-36.6), P <.0001, in men with no change in bone disease. Univariate analysis showed that early ctDNA rise was significantly associated with progression free/overall survival (PFS/OS). In multivariable analysis including ctDNA change from baseline to 3-month treatment, variation of bone metastatic patterns (from oligometastatic to polymetastatic and/or to widespread disease), presence of visceral metastasis, age, PSA, performance status and prior docetaxel therapy, the transition from low- to high-ctDNA within 3 months of starting ARSI therapy was a significant predictor of OS (HR = 2.50, 90% CI, 1.06-5.88, P =.035) and persistent high level of ctDNA was a predictor of PFS (HR = 2.53, 95% CI, 1.10-5.81, P =.028). Metastatic involvement demonstrated that the transition from bone polymetastatic to widespread disease and the presence of visceral metastases were both associated with worse OS (HR = 2.43, 95% CI, 1.10-5.35, P =.028, and HR = 3.40, 95% CI, 1.50-7.66, P =.003, respectively). Prior therapy with docetaxel represented an independent predictor of both PFS and OS (HR = 2.47, 95% CI, 1.40-4.35, P =.002, and HR = 1.78, 95% CI, 1.00-3.15, P =.049, respectively). Conclusions Early ctDNA variation might reflect changes in metastatic burden and, likely, in bone metastatic patterns on ARSI therapy allowing to track pattern of disease progression and to predict outcome.