Doxorubicin + olaratumab is not superior to doxorubicin + placebo in patients with advanced soft tissue sarcomas
William Tap presents the results of the ANNOUNCE-study, a randomised, placebo-controlled, double-blind, phase III trial examining doxorubicin + olaratumab versus doxorubicin + placebo in patients with advanced soft tissue sarcomas. There were no differences in overall survival between the two treatment arms, but progression-free survival was higher in the control arm. Hence, previous results showing that the combination of olaratumab with doxorubicin improved overall survival over doxorubicin alone in patients with advanced soft tissue sarcoma are not confirmed.
Soft tissue sarcomas (STS) are rare and heterogeneous malignancies originating from the mesenchymal precursors. Since the mid-1970s doxorubicin – alone or in combination – has been the standard-of-care for metastatic disease. For patients with newly diagnosed metastatic disease, median survival ranges from 14 to 19 months with 2-year survival rates of 20-30%. Therefore, STS represent an area of unmet medical need.1-4
Olaratumab is a fully human monoclonal IgG1 antibody targeting PDGFRα. In a phase 1B/2 clinical trial it was shown that the combination of olaratumab plus doxorubicin improved overall survival (OS) and progression-free survival (PFS) when compared to single agent doxorubicin. During ASCO 2019, Tap presented the results of the ANNOUNCE study, which aimed to confirm this OS benefit in advanced STS.5
The ANNOUNCE study was a randomised, double-blind, placebo-controlled phase III study, which recruited adult patients with unresectable locally advanced or metastatic STS. Patients were randomised (1:1) to olaratumab (20 mg/kg during cycle 1 and 15 mg/kg during subsequent cycles) or placebo on days 1 and 8 of each 21-day cycle, combined with doxorubicin (75 mg/m2) on day 1 for up to 8 cycles. After completion of 8 cycles patients with stable disease or better continued olaratumab or placebo until progression or toxicity. Primary endpoints were OS in the intent-to-treat (ITT) population and/or leiomyosarcoma (LMS) subset of the ITT population. Secondary endpoints included PFS, response/disease control rates, adverse events, and pharmacokinetics.
A total of 509 patients were randomised: 258 in the experimental arm and 251 in the control arm. In the ITT population, median OS was 20,4 months for the experimental arm and 19,8 months for the control arm (HR 1,05 [95%-CI 0,84-1,30; p=0,69]). In LMS patients, OS was 21,6 months in the experimental arm versus 21,9 months in the control arm (HR 0,95 [95%-CI 0,69-1,31; p=0,76]). There were no differences in OS between the ITT population and the LMS population.
In the ITT population, the median PFS was lower in the investigational arm (5,4 months) compared to the control arm (6,8 months; HR 1,23 [95%-CI 1,01-1,50; p=0,04]). In the LMS population PFS was 4,3 months in the investigational arm and 6,9 months in the control arm (HR=1,22; [95%-CI 0,92-1,63; p=0,17]).
The overall response rates were not significantly different between the 2 treatment arms for both populations. Disease control rates was higher in the control arm (82,6%) compared to the experimental arm (63,0%) for the LMS population (p=0,0011). For the ITT population the disease control rate was 67,4% in the experimental arm and 75,7% in the control arm (p=0,060).
The occurrence of treatment related adverse events was similar between arms.
ANNOUNCE did not confirm, that the combination of olaratumab and doxorubicin followed by olaratumab monotherapy, improves OS over doxorubicin alone in patients with advanced STS. According to the investigators, the inconsistent outcomes between the phase III and phase II studies could be attributed to heterogeneity of the study population within and between studies, differences in study design, or the performance of the control arm. Further analyses are warranted to explore this. STS remain an area of unmet medical need and an important field for discovery and application of new therapies.
1. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014;15(4):415-23.
2. Ryan CW, Merimsky O, Agulnik M, et al. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol 2016;34(32):3898-905.
3. Tap WD, Papai Z, Van Tine BA, et al. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2017;18(8):1089-103.
4. Seddon B, Strauss SJ, Whelan J, et al. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol 2017;18(10):1397-410.
5. Tap WD, Wagner AJ, Papai Z, et al. ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). Presented during ASCO 2019; abstract 9000.