ANNOUNCE: trial | Bending the Curve: Trial by Trial

ANNOUNCE

Effect of doxorubicin plus olaratumab vs doxorubicin plus placebo on survival in patients with advanced soft tissue sarcomas: the ANNOUNCE randomized clinical trial

Phase 3N = 509NCT02451943

Population

509 anthracycline-naive adults with unresectable locally advanced or metastatic soft tissue sarcoma, ECOG performance status 0 to 1 and ejection fraction of 50% or greater

Design

Confirmatory, double-blind, randomised phase 3 trial at 110 sites in 25 countries, September 2015 to December 2018 (final follow-up 5 December 2018); 1:1 to doxorubicin 75 mg/m2 (day 1) with olaratumab (20 mg/kg in cycle 1, 15 mg/kg after) or placebo on days 1 and 8 for up to eight 21-day cycles, then olaratumab or placebo alone. Median follow-up 31 months.

Primary endpoint

Arms

Doxorubicin plus placebo (control, n = 251): Doxorubicin 75 mg/m2 on day 1 plus placebo on days 1 and 8, up to eight 21-day cycles, then placebo
Doxorubicin plus olaratumab (experimental, n = 258): Doxorubicin 75 mg/m2 on day 1 plus olaratumab 20 mg/kg (cycle 1) then 15 mg/kg on days 1 and 8, up to eight 21-day cycles, then olaratumab

People

Tap WD, ANNOUNCE Investigators

OSHR 1.05 (95% CI 0.84–1.30)Δ median OS+0.7 monthsOSHR 0.95 (95% CI 0.69–1.31)Δ median OS−0.3 months

Show the numbers

Results reported for ANNOUNCE
Endpoint	Analysis	Doxorubicin plus olaratumab	Doxorubicin plus placebo	Effect
OSTotal soft tissue sarcoma population (all 509 randomised patients were included in the primary analysis)	primaryTap 2020	median 20.4 months	median 19.7 months	HR 1.05 (95% CI 0.84–1.30)P=.69One of two dual primary endpoints (total soft tissue sarcoma and leiomyosarcoma populations).
OSLeiomyosarcoma population	primaryTap 2020	median 21.6 months	median 21.9 months	HR 0.95 (95% CI 0.69–1.31)P=.76Second of the dual primary endpoints. Leiomyosarcoma made up 46.0% of the randomised patients (abstract).

Results reported for ANNOUNCE
Endpoint	Analysis	Doxorubicin plus olaratumab	Doxorubicin plus placebo	Effect
OSTotal soft tissue sarcoma population (all 509 randomised patients were included in the primary analysis)	primaryTap 2020	median 20.4 months	median 19.7 months	HR 1.05 (95% CI 0.84–1.30)P=.69One of two dual primary endpoints (total soft tissue sarcoma and leiomyosarcoma populations).
OSLeiomyosarcoma population	primaryTap 2020	median 21.6 months	median 21.9 months	HR 0.95 (95% CI 0.69–1.31)P=.76Second of the dual primary endpoints. Leiomyosarcoma made up 46.0% of the randomised patients (abstract).

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
OS	1.05	0.84–1.3
OS	0.95	0.69–1.31

Illustrative — modelled from reported values, not trial data. OS, primary.

Show curves

Doxorubicin plus olaratumab (experimental)
Doxorubicin plus placebo (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Doxorubicin plus olaratumab	Doxorubicin plus placebo
0	100.0%	100.0%
13	64.3%	63.3%
26	41.3%	40.1%
38	27.5%	26.3%
51	17.7%	16.6%

Illustrative — modelled from reported values, not trial data. OS, primary.

Show curves

Doxorubicin plus olaratumab (experimental)
Doxorubicin plus placebo (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Doxorubicin plus olaratumab	Doxorubicin plus placebo
0	100.0%	100.0%
14	63.8%	64.2%
27	42.0%	42.5%
41	26.8%	27.3%
55	17.1%	17.5%

Appears in

2019 Olaratumab: phase 2 survival benefit not confirmed in ANNOUNCE

Sources

Tap WD, Wagner AJ, Schöffski P, Martin-Broto J, Krarup-Hansen A, Ganjoo KN, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020;323(13):1266-1276.
PubMed DOI