Background: Hyaluronan (HA) accumulation in the tumor microenvironment produces elevated tumor pressure, vascular compression, and reduced drug delivery. PEGPH20 degrades HA, increasing the access and therapeutic index of anticancer agents. Methods: In Stage 1 of this phase 2 study, pts with untreated mPDA were randomized 1:1 to PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) vs AG every 28 days. An imbalance in thromboembolic (TE) events in the PAG arm led to a clinical hold (∼40% of pts discontinued PEGPH20), exclusion of pts at high risk for TE events and enoxaparin prophylaxis for all pts. In Stage 2, randomization was 2:1 to PAG vs AG. Tumor HA was tested using a novel assay (VENTANA HA RxDx). Primary endpoints were PFS (evaluable pts) and TE event rate (Stage 2). Secondary endpoints were PFS by HA level and ORR. Results: 279 pts were randomized; 231 are efficacy evaluable. Of 246 pts with HA data, 84 (34%) were HA-High. As of December 16, 2016, the primary PFS endpoint was statistically significant for PAG vs AG (HR 0.73, 95% CI 0.53-1.00; p = 0.048) (Table). PFS in HA-High pts was also statistically significant for PAG vs AG (HR 0.51; 95% CI 0.26-1.00; p = 0.048). ORR in HA-High pts was 46% (PAG) vs 34% (AG). Overall survival in HA-High pts (exploratory) was 11.5 months (mo) (PAG) and 8.5 mo (AG) (HR 0.96, 95% CI 0.57-1.61). TE events were similar (PAG 14% vs AG 10%) with enoxaparin initiation.Table763PPopulationEvents/Total, n Median PFS, monthsHR (95% CI)P valuePAGAGEfficacy Evaluable (n = 231)100/139; 6.065/92; 5.30.73 (0.53, 1.00)0.048HA-High (n = 84)24/49; 9.219/35; 5.20.51 (0.26-1.00)0.048All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Open table in a new tab All grade treatment-related AE included peripheral edema (PAG 63% vs AG 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%). Conclusions: Randomized Phase 2 study met both primary endpoints (PFS and TE event rate), with the largest improvement in the secondary endpoint of PFS in HA-High pts. These data support HA as a potential predictive biomarker for pt selection of PEGPH20, currently investigated in the global Phase 3 HALO 301 study with PFS and OS as co-primary endpoints. NCT01839487 Clinical trial identification: NCT01839487 Legal entity responsible for the study: Halozyme Therapeutics, Inc. Funding: Halozyme Therapeutics, Inc. Disclosure: S.R. Hingorani: Consulting or Advisory Role: Halozyme, Aduro Biotech Research Funding: Halozyme (institution). A. Bullock: Consulting or advisory board participation support: Halozyme, Celgene, and EMD Serono. T. Seery: Consulting or Advisory Role: Bayer Speakers' Bureau: Ipsen, Bayer. L. Zheng: Consult/Advisor: Merrimack; Patents, royalties, Other Intellectual Property: GVAX, Licensed to Aduro Biotech; Stock/Other: Z&L Medical Intl; Res Fund: BM Squibb, Amgen, Iteos Therap, Gradalis, Merck, Halozyme. D. Sigal: Stock or Other Ownership: Novartis, BMS, Ignyta, Halozyme; Honoraria: Novartis, Serond, Halozyme; Speakers' Bureau: Novartis, Celgene, Bayer; Research Funding: Halozyme. F.S. Braiteh: Honoraria, consulting or advisory role, Speaker's Bureau, travels, accommodation, expenses. M. Zalupski: Research Funding: Halozyme, OncoMed, Newlink Genetics. N. Bahary: Consulting or Advisory Role: Bayer/Onyx, EMD Serono Research Funding: New Links Genetics. W. Harris: Consulting or Advisory Role: Neotherma Oncology, Bayer Research Funding: Halozyme, BMS, Exelixis, Argule, Polaris, Medimmune, BTG. J. Pu: Employment: Roche; Research Funding: Roche;Patents, Royalties, Other Intellectual Property: Roche (for author and institution). C. Aldrich: Employment: Roche Tissue Diagnostics. S. Khelifa: Employment: Ventana Medical System Inc.- member of the Roche group; Stock or Other Ownership: Ventana Medical System Inc.- member of the Roche group. W. Wu: Employment: Halozyme Stock or Other Ownership: Halozyme. D. Chondros: Employee of Halozyme Therapeutics, Inc. P. Jiang: Employment: Halozyme; Stock or Other Ownership: Halozyme Therapeutics Inc.; Patents, Royalties, Other Intellectual Property: Halozyme Therapeutics Inc. A. Hendifar: Consulting or Advisory Role: Genentech, Novartis, Ipsen, Perthera Travel, Accommodations, Expenses: Halozyme. All other authors have declared no conflicts of interest.