Table 3.

Key Adjuvant Therapy Trials in Patients with Early High-Risk TNBC, Health Canada, and CADTH Guidance.

	Capecitabine|CREATE-X (n = 910) [39]	Pembrolizumab|KEYNOTE-522 (n = 1174) [40]	Olaparib|OlympiA (n = 1836) [13]
Population	Stage I-III, HER2-negative BC - TNBC or HR+/HER2- No pCR (breast and/or nodes) after NACT	Stage II/III TNBC Any PD-L1 status	gBRCA-mutated HER2-negative eBC - TNBC or HR+/HER2- Received local treatment + NACT or AdjCT x 6 weeks with anthracyclines, taxanes, or both
Definition of “High Risk” per Trial Criteria	No pCR after NACT containing anthracycline, taxane, or both	T1c, N1-2; T2-4 N0-N2 *	TNBC †‡ If AdjCT: LN+ or pT ≥2 cm If NACT: No pCR after NACT
Intervention	Capecitabine 1250 mg/m2 PO BID days 1–14 Q3W x 6–8 cycles Control arm: standard therapy	Experimental arm: NACT: [Pembrolizumab Q3W + Cb + T] x 4 cycles then [Pembrolizumab Q3W + A + C] x 4 cycles Surgery then AdjTx [Pembrolizumab Q3W x 9 cycles] Placebo arm: NACT: [Placebo + Cb + T] x 4 cycles then [Placebo + A + C] x 4 cycles Surgery then AdjTx [Placebo Q3W x 9 cycles]	Olaparib 300 mg PO BID x 1 year 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: TNBC Median follow-up: 15.5 months [40] pCR (ypT0/Tis ypN0): 64.8% vs. 51.2%; Δ 13.6% 18-month EFS: 91.3% vs. 85.3%; Δ 6.0% EFS HR: 0.63 (95% CI, 0.43–0.93) Median follow-up: 39.1 months [43] 3-year EFS: 84.5% vs. 76.8%; Δ 7.7% EFS HR: 0.63 (95% CI, 0.48–0.82); p < 0.001	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 Analyses of DFS/IDFS	Subgroup: ER- and PgR- Median follow-up: 3.6 years [39] DFS: 69.8% vs. 56.1%; Δ 13.7 DFS HR: 0.58 (95% CI, 0.39–0.87) p-value for HR status interaction: 0.21	n/a	Subgroup: TNBC Median follow-up: 2.5 years [13] 3-year IDFS: 86.1% vs. 76.9% IDFS HR: 0.56 (95% CI, 0.43–0.73) Heterogeneity tests: NS Median follow-up: 3.5 years [16,44] 4-year IDFS: 83.1% vs. 75.2%; Δ 7.9% IDFS HR: 0.620 (95% CI, 0.487–0.787) 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: TNBC Median follow-up: 39.1 months [43] 3-year OS: 89.7% vs. 86.9%; Δ 2.8% § OS HR: 0.72 (95% CI, 0.51–1.02) §	ITT Population: HER2- Median follow-up: 3.5 years [16] 4-year OS: 89.8% vs. 86.4%; Δ 3.4% OS HR: 0.68 (98.5% CI, 0.47–0.97); p = 0.009 ‖
Exploratory Subgroup Analyses of OS	Subgroup: ER- and PgR- Median follow-up: 3.6 years [39] OS: 78.8% vs. 70.3%; Δ 8.5% OS HR: 0.52 (95% CI, 0.30–0.90) p-value for HR status interaction: 0.41	n/a	Subgroup: TNBC Median follow-up: 3.5 years [16,44] 4-year OS: 90.1% vs. 86.3%; Δ 4.8% OS HR: 0.640 (95% CI, 0.459–0.884) 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: [41] High-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery CADTH Recommended Population: [54] Per KEYNOTE-522 trial criteria	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)

* According to the AJCC, 7th edition. ^† 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 TNBC criteria are shown here. For high-risk HR+/HER2- disease criteria, refer to Table 4. ^§ Not significant. ^‖ Significance boundary of 0.015. Summary of key trials for adjuvant capecitabine, pembrolizumab, and olaparib in early-stage, high-risk TNBC. A, doxorubicin or epirubicin; AdjCT, adjuvant chemotherapy; AdjTx, adjuvant treatment; BID, bis in die (twice daily); C, cyclophosphamide; CADTH, Canadian Agency for Drugs and Technologies in Health; Cb, carboplatin; DFS, disease-free survival; eBC, early breast cancer; EFS, event-free survival; ER, estrogen receptor; HR, hazard ratio; HR+/HER2-, hormone receptor-positive/human epidermal growth factor receptor 2-negative; IA1/2, interim analysis 1 or 2; IDFS, invasive disease-free survival; ITT, intention-to-treat; LN, lymph node; N, node; NACT, neoadjuvant chemotherapy; NS, not significant; OS, overall survival; pCR, pathological complete response; PgR, progesterone receptor; PD-L1, programmed death ligand 1; PO, per os (orally); Q3W, every 3 weeks; T, paclitaxel; TNBC, triple-negative breast cancer.