Background: The systemic treatment standard of advanced, inoperable STS in elderly pts is single agent DOX. We tested the hypothesis whether PAZ has comparable efficacy to DOX in elderly STS pts, while offering better tolerability. Methods: Key inclusion criteria: age ³60 years, no prior systemic treatment for STS, progressive disease, ECOG 0-2, adequate organ function. DOX 75 mg/m2 q3wks for a total of 6 cycles or PAZ 800 mg OD continuously were given after 1:2 randomization. ECOG 2 and liposarcoma histology were used for stratification. The primary endpoint was progression free survival (PFS) in the per protocol (PP) population. A non-inferiority design was applied with an upper limit of the 95% confidence interval (CI) of less than 1.8. Key secondary endpoints were neutropenia and febrile neutropenia in hierarchical order. EORTC QLQ-C30 was utilized to measure quality of life. Cox regression analysis, ANCOVA and Kaplan-Meier curves were applied (NCT01861951). Results: Between 10/2012 and 03/2016, 39 pts were randomly assigned to DOX and 81 to PAZ. The median follow-up was 11.8 months (mo). The median age was 71 years (range: 60-88). In the PP population, DOX vs. PAZ achieved a PFS of 5.3 vs. 4.4 mo (HR 1.00; 95%CI 0.65-1.53; P = .993), respectively. The incidence of neutropenia CTC grade 4 and neutropenic fever in patients were 56% and 10% for DOX and 0% and 0% for PAZ, respectively. OS was 14.3 vs. 12.3 mo. (HR 1.083; 95%CI 0.68-1.72; P = .735) for the intention to treat population. Most frequent AEs for DOX were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for PAZ fatigue (58.0%), nausea (43.2%) and diarrhea (43.2%). Similar outcome was reported for global EORTC QLQ-C30 measures. Conclusions: This study showed that PAZ was non-inferior compared to DOX, rendering PAZ a putative therapeutic option in the first line treatment of STS of pts above 60 years of age. The distinct AE profile may be used to council pts and tailor therapy to individual needs. Clinical trial information: NCT01861951