Palazestrant Combo Shows Preliminary Activity in ER+/HER2– Breast Cancer

"The study supports the ongoing phase 3 OPERA-02 (NCT07085767) study evaluating 90 mg [once daily] palazestrant in combination with ribociclib for the first-line treatment of [ER-positive, HER2-negative] advanced breast cancer," according to the study authors.

Combining palazestrant (OP-1250) with ribociclib (Kisqali) demonstrated early encouraging activity among patients with advanced estrogen receptor (ER)–positive, HER2-negative breast cancer, according to data from the phase 1b OP-1250-003 study (NCT05508906) presented in a poster session at the European Society for Medical Oncology (ESMO) Congress 2025.1

Among those who received palazestrant at 120 mg, the median progression-free survival (PFS) was 15.5 months (95% CI, 9.0-not evaluable [NE]) for all patients (n = 56) and 12.2 months (95% CI, 7.2-NE) for those with prior receipt of CDK4/6 inhibitors plus endocrine therapy (n = 40). Moreover, the median PFS was 9.2 months (95% CI, 2.1-NE) for those with ESR1 wild-type disease and prior CDK4/6 inhibitors (n = 24) and 13.8 months (95% CI, 7.3-NE) for those with ESR1-mutated disease and prior CDK4/6 inhibitors (n = 14). After a median follow-up of 10.8 months among patients who received palazestrant at 90 mg, the median PFS was not reached.

Data showed an objective response rate (ORR) of 34% (n = 15/44) in the overall population, which included 2 confirmed complete responses (CRs) and 13 confirmed partial responses (PRs). Additionally, the ORR was 42% (n = 5/12) in the 90 mg group, 31% (n = 10/32) in the 120 mg cohort, and 26% (n = 6/23) among those who received palazestrant at 120 mg and prior CDK4/6 inhibitors.

At the time of analysis, 42% (n = 30/72) of patients remained on study treatment. The longest duration of therapy was observed in the 120 mg group at 103 weeks; treatment remains ongoing for this patient.

“Palazestrant was well tolerated when combined with 600 mg of ribociclib. Safety was consistent with the known safety profiles of each drug; palazestrant and ribociclib did not demonstrate any drug-drug interactions,” Nancy U. Lin, MD, associate chief of the Division of Breast Oncology and the founder and director of the Metastatic Breast Cancer Program and the Program for Patients with Breast Cancer Brain Metastases at Dana-Farber Cancer Institute, wrote with coauthors in the poster.1 “The study supports the ongoing phase 3 OPERA-02 (NCT07085767) study evaluating 90 mg [once daily] palazestrant in combination with ribociclib for the first-line treatment of [ER-positive, HER2-negative] advanced breast cancer.”

The OP-1250-003 trial included a dose-escalation portion as well as a dose-expansion phase. In the dose-escalation phase, patients were assigned to receive palazestrant at 120 mg (n = 3), 60 mg (n = 3), or 30 mg (n = 3) plus ribociclib at 600 mg. As part of the dose-expansion portion, patients received 90 mg (n = 16) or 120 mg (n = 53) of palazestrant plus ribociclib.

The trial’s primary end points included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose, pharmacokinetics, and incidence and severity of adverse effects (AEs). Secondary end points included ORR, clinical benefit rate, duration of response, time to progression, and PFS.

Patients 18 years and older with histologically or cytologically confirmed advanced or metastatic breast cancer; ER-positive, HER2-negative disease based on archival tumor tissue sample; and a life expectancy of at least 6 months were eligible for enrollment on the trial.2 Other eligibility criteria included having an ECOG performance status of 0 or 1 and no more than 1 prior line of chemotherapy for locally advanced or metastatic disease.

Across the overall population, the median age was 61 years (range, 25-85), all patients were female (100%), and most were not premenopausal (17%). Additionally, most of the study population had an ECOG performance status of 0 (61%), measurable disease at baseline (68%), visceral disease (54%),1 prior line of therapy in the advanced setting (43%), 1 prior line of endocrine therapy in the advanced setting (53%), and prior treatment with CDK4/6 inhibitors (63%).

Data showed no DLTs in the dose-escalation portion of the trial; the MTD was not reached. Dose reductions of palazestrant were necessary for 2 patients due to single instances of nausea and neutropenia. Investigators reduced doses for both agents in 8 patients and ribociclib alone in 23, with the most common cause being neutropenia.

Among patients who received palazestrant at 120 mg and 90 mg, respectively, the most common any-grade AEs included neutropenia (84% vs 81%), nausea (73% vs 69%), fatigue (54% vs 50%), white blood cell decreases (43% vs 38%), and diarrhea (43% vs 25%). Grade 4 toxicities included neutropenia in 9% of the 120 mg group and 16% of the 90 mg cohort; other grade 4 toxicities in the 120 mg group included decreased white blood cells (2%) and decreased lymphocytes (2%).

References

1. Lin NU, Chien J, Ma C, et al. Palazestrant (OP-1250) plus ribociclib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2−) advanced breast cancer (ABC). Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 502P.
2. Phase 1b study of OP-1250 (palazestrant) in combination with ribociclib, alpelisib, everolimus, or atirmociclib in ER+, HER2- breast cancer. ClinicalTrials.gov. Updated October 22, 2025. Accessed November 5, 2025. https://tinyurl.com/4ftvvtf8