Hingorani SR, et al. - Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. In this current study, patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG), and were examined for tumor HA levels, progression-free survival (PFS; overall) and thromboembolic (TE) event rate. This study met its primary end points of PFS and TE event rate. Notably, patients with HA-high tumors who received PAG, showed the largest improvement in PFS. In addition, a similar TE event rate was observed between the treatment groups in stage 2 of the trial.

• Researchers randomly assigned patients with previously untreated metastatic pancreatic ductal adenocarcinoma to receive PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG).
• They used a novel affinity histochemistry assay to measure tumor HA levels retrospectively.
• Progression-free survival (PFS; overall) and thromboembolic (TE) event rate were primary end points, and overall survival, PFS by HA level, and objective response rate were secondary end points.
• An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated.

• Data showed that a total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity).
• Researchers noted a significant improvement in PFS with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P=.049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P=.048).
• They also found that the objective response rate was 45% vs 31%, and median overall survival was 11.5 vs 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61) in patients with HA-high tumors (PAG v AG).
• In addition, findings demonstrated that muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%) were the most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG).
• Following enoxaparin initiation, comparable TE events were reported (14% PAG v 10% AG).