Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas

Abstract

IMPORTANCEPatients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.OBJECTIVE To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.DESIGN, SETTING, AND PARTICIPANTS ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.INTERVENTIONS Patients were randomized 1:1 to receive doxorubicin, 75 mg/m 2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/ placebo monotherapy.MAIN OUTCOMES AND MEASURES Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. RESULTS Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). CONCLUSIONS AND RELEVANCEIn this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.

Cancer Stem Cells in Soft-Tissue Sarcomas

“…This CSC phenotype was inhibited by the downregulation of PDGFR-α/β levels [44]. Nonetheless, the inhibition of PDGFRα with olaratumab (a human IgG1 antibody targeting PDGFRα) did not showed an enhancement of chemotherapy activity in advanced STS; the phase 3 clinical trial testing the combination of olaratumab and doxorubicin versus doxorubicin did not meet its primary endpoint [7]. Correlative studies associated with this trial are expected, in order to understand if PDGFRβ signaling pathway could have a role in tumor progression after PDGFRα inhibition and to identify those patients who could benefit from doxorubicin plus olaratumab combination.…”

“…Doxorubicin is the backbone for the first-line treatment of metastatic Soft-Tissue Sarcomas (STS). The combination of doxorubicin with other drugs, such as Olaratumab, palifosfamide or evofosfamide, among others have been evaluated in several comparative clinical trials against doxorubicin; however, no significant survival improvement was detected when compared with the single agent [7][8][9]. In spite of initial drug activity, patients finally progress in the majority of the cases.…”

Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma

“…Continued approval was contingent upon verification of clinical benefit in a confirmatory trial; however, the results of the phase 3 trial, ANNOUNCE, did not confirm a clinical benefit for olaratumab combined with doxorubicin compared with doxorubicin monotherapy in patients with advanced or metastatic STS. Hence, olaratumab was no longer recommended for treatment of advanced STS as of January 2019 [15,16].…”

Heterogeneity of Soft Tissue Sarcomas and Its Implications in Targeted Therapy

“…Median overall survival of total soft tissue sarcomas or leiomyosarcoma alone was not significantly different (Total STS 20.4 vs. 19.7 months, leiomyosarcoma 21.6 vs. 21.9 months). They concluded that patients with advanced soft tissue sarcoma have a median overall survival of fewer than 2 years and adding olaratumab to doxorubicin does not improve the overall survival (26).…”