Circulating tumor DNA (ctDNA) dynamics in bone-dominant metastatic castration resistant prostate cancer (mCRPC) treated with radium-223 with or without olaparib: Biomarker analyses from the multicenter, randomized, phase 2, investigator-initiated COMRADE trial.

Abstract

158 Background: We previously reported that olaparib significantly improves radiographic progression-free survival (rPFS) when added to radium-223 for bone-dominant mCRPC in the COMRADE study (NCT03317392). Here, we investigate ctDNA and PSA dynamics by arm from patients on the COMRADE study. Methods: Cell free DNA from banked plasma was sequenced on FoundationOne Monitor as a research use test. ctDNA was quantified as ctDNA tumor fraction (TF). rPFS and overall survival (OS) were assessed by Kaplan-Meier analysis and univariate Cox proportional hazard models, landmarked from the relevant sample collection date; patients with progression before the landmark were excluded. Molecular response (MR) and PSA response (PSA50) were defined as ≥50% decrease from C1D1. Results: Of 113 patients receiving any study treatment, ctDNA results were successfully generated for 102 patients at cycle 1 day 1 (C1D1), of whom 53 were randomized to radium-223+olaparib (Arm A) and 49 to radium-223 alone (Arm B). Across arms, the median ctDNA TF at C1D1 was 16% [Interquartile Range: 1.3-43%]. Across arms, 99 patients had ctDNA results at C2D1: 5 with progression prior to C2D1, 9 patients with no result at C1D1, and 8 with unquantifiable ctDNA change were excluded. ctDNA TF clearance from C1D1 to C2D1 was achieved in 13/77 patients (17%; Arm A: 17%, Arm B: 17%), and 50-99% reduction in 14/77 patients (18%; Arm A: 22%, Arm B: 15%). 15/77 patients (19%; Arm A: 22%; Arm B: 17%) were negative at both timepoints and not included in assessment of MR. MR was associated with significant, favorable PFS (MR: 4.6 months vs No MR: 2.0 months, p=0.01) and OS (MR: 21.2 months vs No MR: 12.2 months, p=0.005) with similar trends within both treatment arms. A greater improvement in rPFS with the addition of olaparib was observed for patients who achieved MR (MR: HR = 0.35 [95% confidence interval (CI): 0.14-0.91]; No MR: HR = 0.65 [95% CI 0.29-1.43]). Similar to TF, baseline PSA was prognostic: when stratified at the median (51.6 ng/mL), patients with lower PSA demonstrated significantly improved rPFS (11.0 vs 3.8 months for low vs high PSA, p<0.0001) and OS (26.6 vs 13.2 months, p<0.0001). Of the 13 patients that ever-achieved PSA50, including after crossover, 69% achieved MR compared to 37% in 49 patients without PSA50. Conclusions: Early MR (by C2D1) was achieved in 35% of patients and strongly associated with improved rPFS and OS while PSA50 responses by C2D1 were not observed in any patients. The rPFS benefit of adding olaparib to radium-223 appeared more evident in those who achieved a MR. Early on treatment ctDNA dynamics in bone-dominant mCRPC may be a valuable tool for treatment decisions with radium-223 therapy. Clinical trial information: NCT03317392 .