Recent randomised phase II trial data have indicated that the addition of 
olaratumab, a novel monoclonal antibody against platelet-derived growth factor 
receptor alpha (PDGFRα), to doxorubicin confers an unprecedented improvement in 
overall survival to patients with anthracycline-naïve advanced soft tissue 
sarcoma. However, this result was disproportionate with progression-free 
survival and response rate, and consequently there are unanswered questions 
regarding the precise mechanism of action of olaratumab. While preclinical data 
show that olaratumab specifically inhibits PDGFRα-mediated oncogenic signalling 
with attendant anti-tumour effects, a lack of correlation between 
pharmacodynamics markers of PDGFRα inhibition and clinical benefit from 
olaratumab suggest other mechanisms beyond modulation of downstream PDGFRα 
molecular pathways. Proposed mechanisms of olaratumab activity include 
engagement of anti-tumour immune responses and alterations of the tumour stroma, 
but these require further evaluation. Meanwhile, the drug-specific contribution 
of cytotoxic agents to olaratumab-containing combinations has yet to be 
characterised. Ongoing and future preclinical and translational studies, coupled 
with the anticipated results of a phase III trial that has completed enrolment, 
should provide greater insight into the efficacy and mode of action of 
olaratumab in soft tissue sarcomas.