Palazestrant + Ribociclib Shows 79% Clinical Benefit After Prior CDK4/6 Exposure in ER+/HER2- Metastatic Breast Cancer

Palazestrant (OP-1250), an oral complete ER antagonist/SERD that degrades both wild-type and mutant ESR1, was dose-escalated to 120 mg once daily alongside standard ribociclib 600 mg (3 weeks on/1 week off) in a Phase 1b/2 study (n = 63; 73% previously on a CDK4/6i; 29% ESR1-mutant). No dose-limiting toxicities emerged, and pharmacokinetics were unchanged for either drug. Treatment-related AEs mirrored ribociclib’s profile (all-grade neutropenia 78%, grade 3/4 46%). Among clinical-benefit–evaluable patients (≥24 weeks on therapy; n = 29) the clinical benefit rate hit 79% overall and 78% in those retreated after CDK4/6i, with partial responses and disease stabilizations lasting up to 12 months. For context, first-line ribociclib + aromatase inhibitor posts a 42% ORR and 32.7 mo median PFS, while endocrine rechallenge after CDK4/6i typically yields CBR ≈30%.