Patient outcomes in WSG-ADAPT according to NATALEE and MonarchE risk criteria.

601 Background: In HR+/HER2- high-risk early breast cancer (eBC), abemaciclib and ribociclib improve the efficacy of standard endocrine treatment (ET), as shown in MonarchE (abemaciclib) and NATALEE (ribociclib). However, the absolute benefit varies according to prognostic factors. We analyzed the outcome of prognostic groups based on MonarchE and/or NATALEE inclusion criteria in the WSG-ADAPT trial considering Recurrence Score (RS, OncotypeDx) and Ki-67 response after preoperative ET. Methods: In WSG-ADAPT (NCT01779206), patients (pts) with clinically high-risk HR+/HER2- eBC (cT2-4 or cN+ or G3 or Ki67 ≥ 15%) initially received a 3-week standard ET before surgery or sequential biopsy. Pts with c/pN2-3 or G3 with Ki67 > 40% were randomized directly to chemotherapy (CT trial) evaluating (neo)adjuvant 4 × paclitaxel q2w vs. 8 × nab-paclitaxel q1w, followed by epirubicin + cyclophosphamide q2w, followed by ET. pN0-1 pts with RS 0-11 or RS 12-25 with ET-response (central Ki67 postET ≤ 10%) received ET alone (ET trial); RS 12-25 pts without ET-response entered CT trial. Pts with N1-3 or T3 or T2, N0 with either Ki-67 ≥ 20% or G3 or RS > 25 were classified as NATALEE high-risk, pts with N2-3 or N1 with either T3-4 or G3 or Ki-67 ≥ 20% were classified as MonarchE high-risk. Results: In the WSG-ADAPT ET trial, 303 (14.2%) and 784 (36.7%) of 2135 pts were classified as MonarchE and NATALEE high-risk, respectively. In the CT trial, 963 (43.2%) and 1572 (70.5%) of 2230 pts were classified as MonarchE and NATALEE high-risk. After 60 months of median follow-up, both high-risk vs. low-risk classifications were highly prognostic for iDFS and dDFS in ET and CT trials. However, low-risk pts (by both classifications) in the ET trial had 5-y iDFS and dDFS of 94.7% and 96.4%, respectively, vs. 90.1% and 93.6% for high-risk by just NATALEE but not by MonarchE criteria (p = n.s.) and vs. 88.3% and 88.9% in both NATALEE and MonarchE high-risk pts (p < 0.001). In the ET-only cohort, survival outcomes were similar between pN0 and pN1 pts at high-risk by NATALEE but not by MonarchE criteria (5-y iDFS of 87.7% vs. 90.2%; p = n.s. and 5-y dDFS of 91.7% vs. 91.9%; p = n.s.). In the CT trial, 5-y iDFS and dDFS rates were 93.9% and 94.9%, respectively, for NATALEE low-risk pts vs. 84.7% and 87.0% for high-risk by NATALEE but not by MonarchE criteria and vs. 77.7% and 79.6% for MonarchE high-risk pts. Conclusions: Among 4365 pts in the WSG-ADAPT trial, subgroups classified as high-risk by NATALEE and MonarchE criteria had poor outcomes. However, N0-1 pts who were high-risk by NATALEE but not MonarchE criteria and pts with RS ≤ 25 and/or ET response had only slightly inferior outcomes compared to low-risk pts with ET therapy alone. Assuming a hazard ratio of 0.7 for a ribociclib effect, as shown in NATALEE, an absolute benefit of approx. 2% fewer dDFS events after 5 years can be assumed in this group based on the WSG-ADAPT experience. Shared decision-making will be key in this intermediate-risk group. Clinical trial information: NCT01779206 .