ANNOUNCE

Background

ANNOUNCE — Phase III confirmatory, double-blind, randomised, placebo-controlled trial. N=509 patients with previously untreated, locally advanced or metastatic soft-tissue sarcoma (all histotypes except GIST), age ≥18 years, ECOG PS 0–1. Enrolled at 110 sites in 25 countries September 2015 – December 2018. Olaratumab (IMC-3G3), a human IgG1 anti-PDGFRα monoclonal antibody, had received FDA accelerated approval in 2016 based on a Phase Ib/II trial (n=133) showing a dramatic OS improvement (HR 0.46, mOS gain +11.8 months). ANNOUNCE was the required confirmatory trial. Registration NCT02451943.

Interventions and follow up

Arm A: Doxorubicin 75 mg/m² q3w + olaratumab 20 mg/kg loading then 15 mg/kg q2w × 8 cycles → olaratumab monotherapy
Arm B: Doxorubicin 75 mg/m² q3w + placebo × 8 cycles → placebo monotherapy
Primary endpoint: Overall survival in total STS population and in leiomyosarcoma (LMS) subgrou
mFollow up: 31 month

Results

mOS (total STS): 20.4 months (olaratumab) vs 19.7 months (placebo); HR 1.05 (95% CI 0.84–1.30), P=.69 — not significant
mOS (LMS subgroup): 21.6 vs 21.9 months; HR 0.95 (95% CI 0.69–1.31), P=.76 — not significant
mPFS: 8.2 vs 8.3 months — not significantly different
ORR: 16.9% vs 11.5% — not significantly different

Adverse events

Main adverse events: Consistent with established doxorubicin toxicity in both arms. Nausea, neutropenia, and fatigue were the most common AEs. No unexpected safety signals with olaratumab. Grade ≥3 AEs numerically similar between arms.

Conclusions

Olaratumab added to doxorubicin did not improve OS compared with doxorubicin + placebo in advanced STS — neither in the unselected population nor in the LMS subgroup. ANNOUNCE provides a cautionary example of accelerated approval based on a small randomized phase II trial whose results were not replicated in a definitive phase III trial, leading to olaratumab's withdrawal from the market in 2019.

Key Limitations

The dramatic Phase Ib/II OS improvement (HR 0.46, mOS +11.8 months) was almost certainly a false positive attributable to small sample size (n=133 total), limited randomisation, and potential selection bias. ANNOUNCE was adequately powered and conclusively negative. The placebo arm's mOS (19.7 months) significantly exceeded historical benchmarks (12–14 months), raising concerns about population enrichment. PDGFRα biomarker selection was not used in either trial. Withdrawal of accelerated approval illustrates risks of surrogate endpoint extrapolation in sarcoma drug development.

Clinical Context

FDA withdrew olaratumab's approval in 2019 following ANNOUNCE results, citing inability to confirm clinical benefit. ANNOUNCE resulted in harmonisation of FDA policies regarding accelerated approval requirements for sarcoma trials. Doxorubicin monotherapy remains standard first-line therapy for advanced STS. Histotype-directed approaches (LMS04/trabectedin for LMS, SU2C-SARC032/pembrolizumab for UPS/LPS) are now preferred investigational strategies. PDGFRα inhibition remains of theoretical interest but is not clinically validated in STS.
Arm A (olaratumab + dox, n=258): Olaratumab 15 mg/kg IV days 1, 8 + doxorubicin 75 mg/m² IV day 1, q3w × 8 cycles; olaratumab maintenance until PD or unacceptable toxicity
Arm B (placebo + dox, n=251): Placebo IV days 1, 8 + doxorubicin 75 mg/m² IV day 1, q3w × 8 cycles; placebo maintenance until PD or unacceptable toxicity

References