Adjuvant treatment directed by the 50-gene Prosigna assay was noninferior to standard chemotherapy followed by endocrine therapy for invasive breast cancer–free survival (IBCFS) in patients with high clinical risk, estrogen receptor (ER)–positive/HER2-negative early breast cancer, according to first results from the phase 3 OPTIMA trial (ISRCTN42400492) presented at the 2026 ASCO Annual Meeting.1
In the per-protocol population, the 5-year IBCFS rate was 90.3% (95% CI, 88.5%-91.8%) in the test-directed arm (n = 2094) vs 91.8% (95% CI, 90.1%-93.2%) in the control arm (n = 2059). This translated to a 1.5% absolute difference in favor of chemotherapy, meeting the trial's prespecified 3% noninferiority margin (adjusted HR, 1.03; 90% CI, 0.85-1.25; P = .006). Investigators concluded that the assay identifies a group comprising approximately two-thirds of such patients who do not have a meaningful chance of benefit from adjuvant chemotherapy.
“[These data] show that Prosigna can safely assist adjuvant chemotherapy decisions for premenopausal women aged at least 40 treated with ovarian function suppression, [as well as] patients with 4 to 9 involved lymph nodes or stage IIIA tumors. Both of these findings are new.” -Robert C. Stein, MA, MB BChir, PhD, FRCP, chief investigator of the OPTIMA trial, stated in his presentation.
Stein also serves as a professor of breast oncology at the UCL Cancer Institute and consultant medical oncologist at University College London Hospitals NHS Foundation Trust in London, England.
How was the OPTIMA trial designed?
OPTIMA is an international, phase 3, randomized noninferiority trial that enrolled patients at least 40 years of age with excised, high clinical risk, ER-positive (immunohistochemistry score greater than 10%), HER2-negative early breast cancer and 0 to 9 involved lymph nodes; receipt of neoadjuvant chemotherapy was prohibited.1,2
Patients were recruited across the United Kingdom, Norway, Sweden, Australia, New Zealand, and Thailand between January 2017 and December 2025. A total of 4420 patients were enrolled onto the study and randomly assigned 1:1 to either the control arm (n = 2215) or a test-directed arm (n = 2214), in which the 50-gene Prosigna assay's risk of recurrence (ROR) score guided treatment. The control arm comprised chemotherapy followed by endocrine therapy; in the test-directed arm, patients with a tumor ROR score above 60 received the same chemoendocrine therapy as the control arm, whereas those with a ROR score of 60 or lower received endocrine therapy alone. Endocrine therapy for premenopausal patients included ovarian function suppression.
The primary end point was IBCFS in the per-protocol population assessed against a 3% absolute noninferiority margin. A key secondary analysis evaluated IBCFS in the per-protocol subpopulation with tumor ROR scores of 60 or lower against a 3.5% margin.
The current readout was a pre-planned, time-driven analysis conducted once all patients had a minimum of 1 year of follow-up, with a median follow-up of 4.0 years (IQR, 2.0-6.0).1 Baseline characteristics were balanced across arms: in the per-protocol population, the median age was 56 years (range, 40-84), 37% of patients were premenopausal, 1% were male, 31% had grade 3 tumors, 73% had 1 to 3 involved nodes, and 19% had 4 to 9 involved nodes. The median ROR score was 50 in the control arm and 49 in the test-directed arm, with 66.0% and 67.8% of patients, respectively, having a ROR score of 60 or lower.
Top Takeaways From the OPTIMA Readout
- In OPTIMA, test-directed therapy with the 50-gene Prosigna was noninferior to chemoendocrine therapy for 5-year IBCFS in both the full per-protocol population (adjusted HR, 1.03; 90% CI, 0.85-1.25; P = .006) and the ROR ≤60 subpopulation (adjusted HR, 1.06; 90% CI, 0.80-1.40; P = .003).
- Investigators estimated that, at most, 2 recurrences would be prevented per 100 patients treated with chemotherapy using Prosigna.
- However, the test can safely assist adjuvant chemotherapy decision-making for premenopausal women at least 40 years of age who received ovarian function suppression; or patients with 4 to 9 involved lymph nodes or stage IIIA disease.
What did the secondary and subgroup analyses show?
In the subgroup of patients with an ROR of at least 60, the 5-year IBCFS rate was 93.6% (95% CI, 91.7%-95.0%) in the test-directed arm (n = 1421) vs 94.8% (95% CI, 93.1%-96.1%) in the control arm (n = 1358). This translated to a 1.2% absolute difference favoring chemotherapy (adjusted HR, 1.06; 90% CI, 0.80-1.40; P = .003). The demonstrated noninferiority limit was 2% in both the full and low-score populations. Distant recurrence–free interval, defined as distant recurrence or death from breast cancer, was similar between arms. A 0.8% 5-year difference favoring chemotherapy
In the full per-protocol population, the 5-year difference was 0.8%, favoring chemotherapy (adjusted HR, 1.04; 90% CI, 0.83-1.30). In the subgroup of patients with an ROR of at least 60, this difference was 1.0% (adjusted HR, 1.17; 90% CI, 0.82-1.66).
Among patients with low ROR score tumors, forest plot analyses showed no evidence of heterogeneity across prespecified subgroups. IBCFS outcomes were consistent regardless of menopausal status and nodal status, although Stein noted that the 4-to-9-node analysis included relatively few patients because the trial recruited a substantial number of patients with large tumors. In premenopausal patients, the HR was 1.04 (95% CI, 0.60-1.80); among postmenopausal patients, the HR was 1.14 (95% CI, 0.76-1.71). Patients with 1 to 3 nodes achieved an HR of 1.11 (95% CI, 0.76-1.64) while those with 4 to 9 nodes had an HR of 1.19 (95% CI, 0.62-2.29).
“We have shown that patients with low ROR score tumors gain minimal, if any, chemotherapy benefits [although] our results apply to the entire population,” Stein summarized during the presentation.
Outcomes were also consistent across anatomical stage groupings, including stage IIIA. Three sensitivity analyses were conducted in the intention-to-treat population, 2 of which were for IBCFS in the full and ROR of at least 60 populations, and 1 which used invasive disease–free survival. Results from these analyses were consistent with the per-protocol findings.
What limitations were noted in regards to the OPTIMA study?
Stein and his colleagues noted several study limitations in their presentation. Because this was a time-driven analysis performed once all patients had at least 1 year of follow-up, 63% of patients had fewer than 5 years of follow-up, which widened confidence intervals. This was particularly evident for subgroup analyses, although most of chemotherapy's effect on recurrence is expected within the first 5 years. The trial population was predominantly White (90%), which the investigators said reflects the breast cancer populations of the participating countries but limits conclusions about Prosigna use in non-White populations. Premenopausal women younger than 40 years were excluded, and a cost-effectiveness analysis is ongoing.
Disclosures: Stein reported receiving honoraria from AstraZeneca, Daiichi Sankyo/AstraZeneca, Gilead Sciences, Lilly, Novartis, and Pfizer; and research funding from AstraZeneca, Novartis, and Pfizer.
References
- Stein RC, Makris A, Macpherson IR, et al. First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer: a pre-planned time-driven analysis. J Clin Oncol. 2026;44(suppl 16):500. doi:10.1200/JCO.2026.44.16_suppl.500
- Optimal personalised treatment of early breast cancer using multiparameter analysis (OPTIMA). ISRCTN Registry. Updated December 15, 2025. Accessed May 30, 2026. https://doi.org/10.1186/ISRCTN42400492
