HRS-8080, an oral selective estrogen receptor degrader (SERD), in ER+/HER2− advanced breast cancer (aBC) with <i>ESR1</i> mutations ( <i>ESR1</i> m): Results from a first-in-human phase 1 trial.

Abstract

1069 Background: HRS-8080 is a novel, potent oral SERD that binds ER with high affinity. We conducted a multi-part, first-in-human phase 1 trial of HRS-8080 in ER+/HER2- aBC, and here report findings in the ESR1 m subset from the dose-escalation/expansion parts for HRS-8080 monotherapy. Methods: This multicenter, open-label, single-arm phase 1 study enrolled patients (pts) with locally advanced/metastatic ER+/HER2- BC previously treated with ≥1 line of endocrine therapy (ET) and ≤2 lines of chemotherapy for aBC; ESR1 m status was centrally assessed by ctDNA. In Part A (i3+3 design), pts received HRS-8080 QD (50, 150, 300, 600, or 900 mg) or BID (300 mg); in Part B, 300 mg BID/600 mg QD were selected for expansion. Safety was a primary objective. Results: 40 pts with ESR1 m were treated (≥2 prior lines of therapy, 70.0%; ≥2 prior lines of ET for aBC, 42.5%; chemotherapy for aBC, 57.5%), including 32 at expansion doses. Overall, grade ≥3 treatment-related adverse events (TRAEs) occurred in 8 (20.0%) of 40 pts; the most common were decreased lymphocyte count and decreased neutrophil count (2 [5.0%] pts each). TRAEs led to dose reduction in 1 (2.5%) pt. There were no treatment-related deaths. Efficacy in the ESR1 m subset is shown in Table 1. At expansion doses of 300 mg BID/600 mg QD, the confirmed objective response rate was 34.4% (11/32; 95% CI 18.6–53.2) and the disease control rate was 75.0% (24/32; 95% CI 56.6–88.5). Median duration of response was 11.1 mo (95% CI 6.5–not reached), with over half of responses remained ongoing. As of data cutoff, 21 (65.6%) pts had disease progression or died; median progression-free survival was 7.2 mo (95% CI 3.6–11.1). Conclusions: HRS-8080 demonstrated a favorable safety and tolerability profile and encouraging antitumor activity in ESR1m ER+/HER2− aBC, supporting ongoing clinical development both as monotherapy and in combination regimens. Clinical trial information: NCT05189717 . Key baseline characteristics and efficacy in ESR1 m subset. * 50mg QD~300mg QD (n=6) 300mg BID+600mg QD (n=32) 900mg QD(n=2) All patients(n=40) ≥2 prior lines of therapy, n (%) 5 (83.3) 21 (65.6) 2 (100.0) 28 (70.0) ≥2 prior lines of ET for aBC, n (%) 3 (50.0) 13 (40.6) 1 (50.0) 17 (42.5) Chemotherapy for aBC, n (%) 5 (83.3) 16 (50.0) 2 (100.0) 23 (57.5) Confirmed ORR, %(n/N; 95% CI) 0 34.4(11/32; 18.6–53.2) 0 27.5(11/40; 14.6–43.9) Median DoR, mo (95% CI) – 11.1 (6.5–NR) – 11.1 (6.5–NR) Median PFS, mo (95% CI) 2.2 (1.7–5.5) 7.2 (3.6–11.1) NR (9.2–NR) 7.2 (3.6–10.9) Median follow-up, mo (range) 3.0 (0.3–24.6) 6.7 (1.5–34.3) 21.3 (10.4–32.2) 6.6 (0.3–34.3) Data cutoff, Dec. 18, 2025. * Patients relapsed after 24 months if receiving adjuvant ET, and had disease progression ≥6 months of the first-line ET in the advanced setting. aBC, advanced breast cancer; DoR, duration of response; ET, endocrine therapy; NR, not reached; ORR, objective response rate; PFS, progression-free survival.