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Palazestrant is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that completely blocks ER-driven transcriptional activity. Palazestrant combined with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut models, and in brain metastasis animal models. In a phase 1/2 monotherapy study of ER+, HER2- metastatic breast cancer (MBC) patients (pts), palazestrant was well tolerated, demonstrated encouraging antitumor efficacy and favorable pharmacokinetics (PK) at the 120 mg once daily (qd) recommended phase II dose (Lin et al. ESMO 2023 MO382). This study evaluates the safety, PK, and antitumor activity of palazestrant plus ribociclib in pts with ER+, HER2– MBC (NCT05508906). Pts with evaluable ER+, HER2– advanced or MBC with ≤2 prior endocrine therapies (prior CDK4/6 inhibitors CDK4/6i allowed) and ≤1 prior line of chemotherapy were included. Patients received palazestrant at 30, 60, or 120 mg qd in combination with ribociclib (600 mg qd on a 3-weeks-on, 1-week-off schedule). As of January 02, 2024, 33 pts were on study for ≥4 weeks, 27 pts received 120 mg palazestrant. Twenty-seven pts (82%) received prior CDK4/6i: 24 prior palbociclib, 5 prior ribociclib and 4 prior abemaciclib; 7 pts (21%) received two prior lines of CDK4/6i. At time of the data cutoff, 26 pts (79%) were on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) were nausea, neutropenia (G4: 2 pts; 6%), WBC count decreased, fatigue, anemia, and diarrhea. Most TEAEs were grade 1-2 and consistent with the known safety profiles of each drug. Tumor response and prolonged disease stabilization, including in those with prior CDK4/6i, were reported at time of data cutoff. No effect of palazestrant on ribociclib PK and no meaningful effect of ribociclib on palazestrant PK were observed, consistent with previously reported data. Palazestrant plus ribociclib was well tolerated and enrollment is ongoing. No new safety signals were identified. Antitumor activity and clinical benefit, including in heavily pretreated patients, were observed. Updated data will be presented.
Borges et al. (Wed,) studied this question.