Palazestrant (OP-1250) plus ribociclib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) advanced breast cancer (ABC)

Document Type

Conference Proceeding

Publication Date

9-1-2025

Publication Title

Ann Oncol

Keywords

Oncology

Abstract

Background: Endocrine resistance is a major challenge for ER+, HER2- ABC, and novel endocrine therapies (ETs) that can overcome resistance are needed. Palazestrant is an oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD) that blocks estrogen receptor activity regardless of ESR1 mutation status. This phase 1/2 study evaluates safety, PK, and antitumor activity of palazestrant plus ribociclib in patients (pts) with ER+, HER2– ABC (NCT05508906). Methods: Pts with evaluable ER+, HER2– ABC with ≤2 prior ETs (prior CDK4/6 inhibitors [CDK4/6i] allowed) and ≤1 prior line of chemotherapy were included. In dose escalation, pts received palazestrant 30-120 mg qd with ribociclib (600 mg); 90 or 120 mg of palazestrant were administered in dose expansion. Results: As of April 03, 2025, 56 pts received 120 mg and 16 pts received 90 mg palazestrant plus ribociclib. The most common treatment-related AEs (TRAEs) among the 72 pts treated were neutropenia (83%), nausea (74%), fatigue (53%), decreased WBC (42%), diarrhea (39%), anemia and vomiting (35% each). The majority of TRAEs were grade 1-2. The most common grade 3-4 TRAE was neutropenia (50% grade 3 and 10% grade 4). No clinically meaningful effect of palazestrant on ribociclib PK or ribociclib on palazestrant PK was observed, consistent with prior reports. In the 120 mg palazestrant cohort, 66% pts had measurable disease and 57% had visceral disease at baseline. ESR1 mutations at baseline were in 26% pts. 75% pts had prior ET, 39% had prior fulvestrant and 71% pts had prior CDK4/6i for ABC (16% had two prior CDK4/6i). At the cut-off date, 22 pts (39%) remain on treatment with longest duration ∼22 months and ongoing. Among pts with measurable disease, ORR was 34% in all and 30% in pts with prior CDK4/6i. With median follow-up at 16 months, median PFS was 13.8 months (90% CI [9.2 - NE]) for all and 12.2 months (90% CI [7.2 – NE]) for those who received prior CDK4/6i. Conclusions: Palazestrant and ribociclib safety were consistent with the previous reports for each drug in ABC and with robust efficacy in all pts and in those with prior CDK4/6i. A first-line phase 3 trial (OPERA-02) is planned.

Volume

36

First Page

1

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