Background: SERDs competitively antagonize and degrade the ER and can block signaling in ER-dependent tumors resistant to standard endocrine therapy (ET). This study (NCT03284957) investigates SAR439859, a potent oral SERD, in ER+/HER2- mBC. We present pooled dose escalation/expansion (Part A/B) data for SAR439859. Methods: Postmenopausal patients (pts) with ER+/HER2- mBC treated for ≥ 6 mos with prior ET received SAR439859 ≥ 150 mg QD (Part A) or 400 mg QD (Part B). Chemotherapy and targeted therapy in the advanced setting were allowed. Objective response rate (ORR; RECIST v1.1), clinical benefit rate (CBR; complete or partial response [PR] or stable disease [SD] ≥ 24 weeks), safety, and pharmacokinetics (PK) were assessed. Results: Pts (n = 62; Part A, 13; Part B, 49) had a median age of 63 yrs (range 37–88) and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral disease. All had prior ET, 74.2% had prior targeted therapy and 48.4% had ≥ 3 prior lines in the advanced setting. 61.3% of pts had treatment-related adverse events (TRAEs), all grade 1–2. Most frequent: hot flush (16.1%), constipation, arthralgia (both 9.7%), decreased appetite, vomiting, diarrhea, nausea (all 8.1%), fatigue (6.5%). No pts discontinued due to AEs. CBR was 35.6% overall, with antitumor activity irrespective of ESR1 mutation status (Table). In pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14), ORR was 21.4% and CBR 64.3%. PK data for Part B and ESR1 mutation data will be provided. Conclusions: SAR439859 had a favorable safety profile with limited TRAEs. In these heavily pre-treated pts (prior targeted therapy in 74.2%), ORR and CBR were similar to historical fulvestrant performance in pts with no prior targeted therapy. Encouraging ORR and CBR in pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14; ORR 21.4%; CBR 64.3%) supports SAR439859 development in earlier lines of therapy. Clinical trial information: NCT03284957.

^aESR1 status available for n = 58