Palazestrant Monotherapy Moves Into Phase 3 Examination in ER+, HER2– Breast Cancer

Following encouraging activity shown in a phase 1/2 study (NCT04505826), the phase 3 OPERA-01 trial (NCT06016738) is being conducted to further evaluate palazestrant (OP-1250) for the treatment of patients with estrogen receptor (ER)–positive, HER2-negative advanced or meta- static breast cancer.^1,2

“Palazestrant has dual mechanisms of action; it’s an oral CERAN [complete estrogen receptor antagonist] and SERD [selective estrogen receptor degrader],” Heather McArthur, MD, MPH, FASCO, said in an interview with OncologyLive. “The hope is that by interfering with the estrogen modulation of ER-positive metastatic breast cancer, [this agent] could have more effective [activity] compared with conventional, standard-of-care [SOC] therapeutics.”

McArthur is the clinical director of breast cancer and the Komen Distinguished Chair in Clinical Breast Cancer Research at the University of Texas Southwestern Medical Center in Dallas.

PHASE 1/2 DATA SHOW FEASIBILITY OF PALAZESTRANT IN ER+, HER2– BREAST CANCER

Palazestrant monotherapy was previously examined in a first-in-human,
open-label, multicenter phase 1b/2 trial that enrolled patients with ER-positive, HER2-negative metastatic breast cancer who received at least 1 prior line of endocrine therapy for advanced or metastatic disease for at least 6 months continuously.² Patients were also required to have received 2 or fewer prior chemotherapy regimens for metastatic disease, an ECOG performance status of 0 or 1, and evaluable disease.

In the phase 1, dose-escalation portion of the trial, patients received palazestrant at doses ranging from 30 mg to 300 mg daily; 60 mg and 120 mg daily were selected for the phase 1b dose-expansion portion. In phase 2, patients received the agent at the recommended phase 2 dose (RP2D) of 120 mg per day.

The median age among all patients who received either 60 mg or 120 mg of palazestrant (n =116) was 61.0 years (range, 30-85). All patients were female and 95.7% received a prior CDK4/6 inhibitor. The number of prior lines of therapy in the advanced setting was 1 (25.9%), 2 (30.2%), 3 (21.6%), 4 (13.8%), and at least 5 (8.6%).

Findings from the trial revealed that response-evaluable patients treated at the 60-mg dose (n =26) experienced an overall response rate (ORR) of 11.5% and a clinical benefit rate (CBR) of 19.2% (95% CI, 6.6%-39.4%). The CBR among patients with ESR1-mutated disease (n =13) was 23.1% (95% CI, 5.0%-53.8%).

Patients with measurable disease who received the 120-mg dose (n =66) achieved an ORR of 7.6%. The CBR was 45.7% (95% CI, 33.7%-58.1%) among all patients who received the 120-mg dose (n =70) and 58.6% (95% CI, 38.9%-76.5%) among patients with ESR1-mutated disease (n =29). The median progression-free survival (PFS) at this dose level was 4.8 months (95% CI, 3.5-7.1), and the 6-month PFS rate was 39%. These respective figures were 5.6 months (95% CI, 4.8-not evaluable) and 47% among patients with ESR1-mutated disease.

In terms of safety, patients who received palazestrant at the RP2D (n =86) experienced any-grade treatment-emergent adverse effects (TEAEs) at a rate of 95.3%. The most common any-grade TEAEs included nausea (62.8%), vomiting (29.1%), and fatigue (25.6%). Overall, 7 patients discontinued treatment due to adverse effects (AEs), 5 of which were attributed to palazestrant.

“We saw encouraging response rates in heavily pretreated patients,” McArthur noted. “The AEs that occurred were typically low grade. There was grade 4 neutropenia in 6% of patients [who received the 120-mg dose], but, overall, this was an extremely well-tolerated option.”

PHASE 3 OPERA-01 TRIAL OF PALAZESTRANT IS UNDERWAY

OPERA-01 is an international, multicenter, randomized, open-label study that is enrolling patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer with measurable disease or evaluable bone disease.^1,3 Eligible patients must also have received 1 to 2 prior lines of endocrine therapy for advanced breast cancer, a prior CDK4/6 inhibitor, have an ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. The study includes male and female patients; male and pre- or perimenopausal female patients must be willing to receive a gonadotropin-releasing hormone or luteinizing hormone–releasing hormone agonist.

In the experimental arm, patients will receive oral palazestrant at 90 mg once daily via 28-day cycles. In the active comparator arm, patients will receive SOC endocrine therapy with fulvestrant at 500 mg on days 1 and 15 of cycle 1, and then on day 1 of every subsequent cycle, oral anastrozole at 1 mg once daily, oral letrozole at 2.5 mg once daily, and oral exemestane at 25 mg once daily, all via 28-day cycles.

“OPERA-01 had 2 phases, and the study was on hold as we decided on a dose to move forward with for the more robust phase of the study,” McArthur explained. “[The 90-mg] dose was selected from our first experience [with palazestrant], and the study reopened at a fixed dose.”

The primary end point is PFS per blinded independent central review in the ESR1-mutated and -unmutated patient populations. Overall survival is the study’s key secondary end point; other secondary end points include investigator- assessed PFS, ORR, CBR, duration of response, safety and tolerability, pharmacokinetics, and patient-reported outcomes.³

In August 2025, Olema Oncology announced that the topline data from OPERA-01 are expected to be reported in the second half of 2026.4 Additionally, palazestrant is also being evaluated in combination with ribociclib (Kisqali) for the frontline treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer in the phase 3 OPERA- 02 trial (NCT07085767).

“I’m excited to see palazestrant move into the first-line setting [as monotherapy and] together with CDK4/6 inhibitor therapy,” McArthur said. “It’s exciting to see a promising agent move up earlier in the course of disease, because we expect even better response rates. We are in an era of unprecedented successful drug development and rapid improvement in clinically important end points such as PFS and OS. It is an optimistic time to be treating [patients with] breast cancer.

References

1. Pistilli B, Sohn J, Schmid P, et al. OPERA-01: a randomized, open- label, phase 3 study of palazestrant (OP-1250) monotherapy vs standard-of-care for ER+, HER2- advanced or metastatic breast cancer patients after endocrine therapy and CDK4/6 inhibitors. J Clin Oncol. 2025;43(suppl 16):TPS1131. doi:10.1200/ JCO.2025.43.16_suppl.TPS1131
2. Hamilton EP, Patel MR, Borges VF, et al. Palazestrant, a novel oral complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), in patients with ER+/HER2- advanced or metastatic breast cancer: phase 1/2 study results. Breast Cancer Res. 2025;27(1):119. doi:10.1186/ s13058-025-02049-y
3. OP-1250 (palazestrant) vs standard of care for the treatment of ER+/HER2- advanced breast cancer (OPERA-01). ClinicalTrials. gov. Updated August 29, 2025. Accessed August 29, 2025. https://www.clinicaltrials.gov/study/NCT06016738
4. Olema Oncology reports second quarter 2025 financial and operating results. News release. Olema Oncology. August 11, 2025. Accessed August 28, 2025. https://ir.olema.com/news- releases/news-release-details/olema-oncology-reports-second- quarter-2025-financial-and