Survival rates for
pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant
tumor and one of the explanations for this is attributed to desmoplasia that impedes
drug delivery. Based on this, stromal modifying agent such as
Pegvorhyaluronidase alfa (
PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high
hyaluronic acid (HA) expressing
tumors, the phase III HALO 301 study failed to miss it's primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low
tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the
tumor stroma may be a physical barrier hampering
drug delivery, it may also have protective effects in restraining
tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and
cancer cells are warranted.