Table 4.

Key Adjuvant Therapy Trials in Patients with High-Risk HR+/HER2- Early Breast Cancer, Health Canada, and CADTH Guidance

	Capecitabine|CREATE-X (n = 910) [39]	Abemaciclib|monarchE (n = 5367) [55]	Olaparib|OlympiA (n = 1836) [13]
Population	Stage I-III, HER2-negative BC - TNBC or HR+/HER2- No pCR (breast and/or nodes) after NACT	HR+/HER2- high-risk eBC after surgery and RT and/or AdjCT/NACT	gBRCA-mutated HER2-negative early breast cancer TNBC or HR+/HER2- Received local treatment + NACT or AdjCT x 6 wk with anthracyclines, taxanes, or both
Definition of “High Risk” per Trial Criteria	No pCR, after NACT containing anthracycline, taxane, or both	Cohort 1 ≥4 LN+ or 1–3 LN+ and ≥1 of the following: -T ≥5 cm -Grade 3 Cohort 2 1–3 LN+ and Ki-67 ≥20%	HR+/HER2- *† If AdjCT: ≥4 LN+ If NACT: No pCR with a CPS + EG score ≥3
Intervention	Capecitabine 1250 mg/m2 PO BID days 1–14 Q3W x 6–8 cycles Control arm: standard therapy	Abemaciclib (150 mg BID x ≤2 years) +SOC ET (5–10 years as clinically indicated) Control arm: SOC ET (5–10 years as clinically indicated)	Olaparib 300 mg PO BID x 1 year Control arm: Placebo PO x 1 year
Primary Endpoint	ITT Population: HER2- Median follow-up: 3.6 years [39] 3-year DFS: 82.8 vs. 73.9%; Δ 8.9% 5-year DFS: 74.1 vs. 67.6%; Δ 6.5% DFS HR: 0.70 (95% CI, 0.53–0.92); p = 0.01	ITT Population: HR+/HER2- Median follow-up: 15.5 months [55] 2-year IDFS: 92.2 vs. 88.7%; Δ 3.5% IDFS HR: 0.75 (95% CI, 0.60–0.93; p = 0.01) Median follow-up: 42 months [61] 4-year IDFS: 85.8% vs. 79.4%; Δ 6.4% IDFS HR: 0.664 (95% CI, 0.578–0.762)	ITT Population: HER2- Median follow-up: 2.5 years [13] 3-year IDFS: 85.9 vs. 77.1%; Δ 8.8% IDFS HR: 0.58 (99.5% CI, 0.41–0.82); p < 0.0001 Median follow-up: 3.5 years [16] 4-year IDFS: 82.7% vs. 75.4%; Δ 7.3% IDFS HR: 0.63 (95% CI, 0.50–0.78)
Exploratory Subgroup Analysis of DFS/IDFS	Subgroup: ER+ or PgR+ Median follow-up: 3.6 years [39] DFS: 76.4% vs. 73.4%; Δ 3.0% DFS HR: 0.81 (95% CI, 0.55–1.17) p-value for HR status interaction: 0.21 (NS)	CADTH Population: ‡ Cohort 1, Ki-67 ≥20% [29,56] Median follow-up: 27 months IDFS HR: 0.63 (95% CI, 0.49–0.80)	Subgroup: HR+/HER2- Median follow-up: 2.5 years [13] 3-year IDFS: 83.5 vs. 77.2% IDFS HR: 0.70 (95% CI, 0.38–1.27) Heterogeneity tests: NS Median follow-up: 3.5 years [16,44] 4-year IDFS: 80.1% vs. 76.6%; Δ 3.5% IDFS HR: 0.680 (95% CI, 0.402–1.134) p-value for heterogeneity: 0.754 (NS)
Secondary Endpoint: OS	ITT Population: HER2-Median follow-up: 3.6 years [39] 5-year OS: 89.2 vs. 83.6%; Δ 5.6% OS HR: 0.59 (95% CI, 0.39–0.90)	ITT Population: HR+/HER2- Median follow-up: 27 months [55] ITT, OS HR: 1.091 (95% CI, 0.818–1.455) Median follow-up: 42 months [61] ITT, OS HR: 0.929 (95% CI, 0.748–1.153); p = 0.50	ITT Population: HER2-Median follow-up: 3.5 years [16] 4-year OS: 89.8 vs. 86.4% (ITT); Δ 3.4% OS HR: 0.68 (98.5% CI, 0.47–0.97); p = 0.009 §
Exploratory Subgroup Analysis of OS	Subgroup: ER+ or PgR+Median follow-up: 3.6 years [39] OS: 93.4% vs. 90.0%; ∆ 3.4% OS HR: 0.73 (95% CI, 0.38–1.40) p-value for HR status interaction: 0.41 (NS)	CADTH Population: ‡ Cohort 1, Ki-67 ≥20% [29,56] Median follow-up: 27 months OS HR: 0.767 (95% CI, 0.511–1.152)	Subgroup: HR+/HER2-Median follow-up: 3.5 years [16,44] 4-year OS: 88.1% vs. 86.3% ∆ 1.8% OS HR: 0.897 (95% CI, 0.449–1.784) p-value for heterogeneity: 0.381 (NS)
Health Canada Indication and CADTH Recommendation	No indication for early breast cancer approved by Health Canada [42] Funded in most provinces [45,46,47,48,49,50,51,52,53]	Health Canada: [57] In combination with ET for the adjuvant treatment of HR+/HER2-, LN+ eBC at high risk of disease recurrence based on clinicopathological features and a Ki-67 score ≥20% CADTH Recommended Population: [56] HR+/HER2- eBC with Ki-67 ≥20% and one of the following: -≥4 LN+ -1–3 LN+ and Grade 3 -1–3 LN+ and T ≥ 5	Health Canada: [8] Patients with gBRCA-mutated, HER2-negative high risk eBC who have been treated with neoadjuvant or adjuvant chemotherapy CADTH Recommended Population: [30] Per OlympiA trial criteria (Section 2.1, Table 1)

* Risk assessment was performed at the time of surgery. ^† The OlympiA trial included patients with both TNBC and HR+/HER2- breast cancer. Only high-risk HR+/HER2- disease criteria are shown here. For high-risk TNBC criteria, refer to Table 3. ^‡ A gated hierarchical testing strategy included IDFS in patients with a Ki-67 score ≥20% from cohort 1 alone [29]. ^§ Significance boundary of 0.015. Summary of key trials for adjuvant capecitabine, abemaciclib, and olaparib in high-risk, HR+/HER2- early breast cancer. AdjCT, adjuvant chemotherapy; BID, bis in die (twice daily); CADTH, Canadian Agency for Drugs and Technologies in Health; DFS, disease-free survival; eBC, early breast cancer; HR, hazard ratio; HR+/HER2-, hormone receptor-positive/human epidermal growth factor receptor 2-negative; IA1/2, interim analysis 1 or 2; ITT, intention-to-treat; LN, lymph node; NACT, neoadjuvant chemotherapy; NS, not significant; Q3W, every 3 weeks; RT, radiation therapy; SOC ET, standard of care endocrine therapy.