Background: Hyaluronan (HA) and collagens are major constituents of the ECM. HA accumulation in the tumor microenvironment may result in elevated interstitial fluid pressure, vascular compression, and reduced drug delivery and immune cell access. PEGPH20 degrades HA, increasing tumoral access for therapeutics and immune cells. Liquid biopsies reflecting ECM remodeling may provide a non-invasive approach to identify pts most likely to benefit from PEGPH20 therapy. Methods: Peptide markers of ECM remodeling (C3M, PRO-C3, PRO-C6, and VCANM) were measured using baseline plasma samples from Stage 1 (n=94) and Stage 2 (n=95) of HALO-109-202 (NCT01453153), a Phase 2, open-label, randomized study of PEGPH20 + A + G (PAG) vs AG in previously untreated pts with Stage IV PDAC. Univariate and ratio analyses were conducted to correlate biomarker levels with survival outcomes (PFS, OS). Results: The ratio of C3M (MMP degradation fragment of type-III collagen) vs PRO-C3 (N-terminal pro-peptide of type-III collagen) predicted for PFS benefit in PEGPH20-treated pts in Stage 1. The predictive value of this ratio for PFS and OS of PEGPH20-treated pts was further validated in Stage 2. Conclusions: This supports development of a liquid biopsy-based companion diagnostic for selecting pts that may benefit from PEGPH20.