Phase II Breast Cancer Trial: Large Declines in Ki67 Index Seen With Oral Selective Estrogen Receptor Degrader

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In the phase II coopERA Breast Cancer trial, which evaluated two endocrine neoadjuvant therapies in estrogen receptor–positive, HER2-negative early breast cancer, the oral selective estrogen receptor degrader giredestrant led to a greater reduction in Ki67 level—a measure of cancer cell proliferation—than anastrozole, though the difference reflected a “strong trend” and not statistical significance, according to an interim analysis presented at the European Society for Medical Oncology (ESMO) Congress 2021 by Sara A. Hurvitz, MD.1

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

“At week 2, the relative Ki67 reduction was greater, and more tumors exhibited complete cell-cycle arrest, with giredestrant than with anastrozole,” said Dr. Hurvitz, Director of the Breast Cancer Clinical Research Program, Co-Director of the Santa Monica University of California, Los Angeles (UCLA) Outpatient Hematology/Oncology Practice, and Professor of Medicine at the David Geffen School of Medicine at UCLA.

“This is the first trial to report comparative findings between an oral selective estrogen receptor degrader and an aromatase inhibitor and the first showing activity of an oral selective estrogen receptor degrader over an aromatase inhibitor. The study will continue to the primary analysis,” she said.

Strong Trend

According to the centrally assessed geometric mean, the mean relative Ki67 reduction from baseline to week 2 was 80% with giredestrant vs 67% with anastrozole (P = .0222). “This is a strong trend but did not meet our prespecified crossing boundary for statistical significance at the interim analysis,” Dr. Hurvitz acknowledged. “The prespecified critical P value for statistical significance for this interim analysis was .01029.”

Additionally, with giredestrant more tumors displayed complete cell-cycle arrest, a shutdown of cell proliferation (defined as Ki67 ≤ 2.7%): 25.0% vs 5.1%. Consistent Ki67 suppression was observed in patients with baseline Ki67 levels ≥ 20% and < 20%, Dr. Hurvitz reported.

Declines in Ki67 levels have been linked with better long-term efficacy outcomes in early-stage breast cancer. Giredestrant is a highly potent, nonsteroidal, oral selective estrogen receptor degrader that has demonstrated antitumor activity as a single agent and in combination with the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib in metastatic breast cancer. The standard dose is 30 mg.

Developers of several novel selective estrogen receptor degraders are aiming to provide a more patient-friendly oral alternative to intramuscular fulvestrant. Giredestrant, amcenestrant, camizestrant and elacestrant are in phase III trials, with some studies evaluating them in combination with CDK4/6 inhibitors.

About the coopERA Trial

The neoadjuvant phase II coopERA study enrolled 202 postmenopausal patients with treatment-naive estrogen receptor–positive HER2-negative early breast cancer. All patients had a baseline Ki67 score ≥ 5%, tumors ≥ 1.5 cm at presentation, and available baseline tumor tissue.

There were 109 patients randomly assigned 1:1 to receive monotherapy with either oral giredestrant at 30 mg daily, or oral anastrozole at 1 mg daily, during a 2-week window-of-opportunity phase. Patients then went on to receive 16 cycles of either giredestrant or anastrozole daily, at the same dose, combined with oral palbociclib at 125 mg daily for days 1 to 21 of a 28-day cycle.

Baseline characteristics were comparable between the arms. About half the patients had stage IIA disease at diagnosis; most had negative lymph nodes, T2 tumors, and co-expression of progesterone.

The primary endpoint of the study was centrally assessed geometric mean relative Ki67 score change from baseline to week 2 during the window-of-opportunity phase. Other key endpoints included safety and complete cell-cycle arrest, defined as a Ki67 score ≤ 2.7% at week 2.

Other Findings of the Interim Analysis

The efficacy-evaluable population (having central Ki67 scores at both baseline and week 2) included 44 patients on the giredestrant arm and 39 on the anastrozole arm. Most patients in each study arm had a mean baseline Ki67 level of at least 20%. A total of 10 patients in the giredestrant arm and 5 patients in the anastrozole arm had a mean baseline Ki67 level of less than 20%. The treatments were evaluated in both those subsets.

“Giredestrant was associated with a higher mean reduction in Ki67 score, regardless of Ki67 level,” she reported. Mean relative reduction was 83% in those with baseline Ki67 levels of at least 20% vs 71% with anastrozole (P = .0222), and in patients with Ki67 levels less than 20%, the mean reduction was 65% with giredestrant and 24% with anastrozole (P = .1087).


  • The phase II coopERA Breast Cancer trial compared neoadjuvant therapy with the oral selective estrogen receptor degraders giredestrant vs anastrozole in 109 women with early estrogen receptor–positive, HER2-negative breast cancer.
  • The primary endpoint, a reduction in Ki67 level, was greatest for the giredestrant group, though the difference did not achieve statistical significance.
  • Additionally, with giredestrant, more tumors displayed complete cell cycle arrest, a shutdown of cell proliferation (defined as Ki67 level ≤ 2.7%).

The trend was similar for tumors achieving complete cell-cycle arrest at week 2: 15.9% vs 5.1% in the high-Ki67 group and 9.1% vs 0, respectively, in the lower baseline group, Dr. Hurvitz reported. In the overall population, the relative reduction in mean Ki67 from baseline was 13% greater with giredestrant; the difference in achievement of complete cell-cycle arrest was almost 20%.

Value of Ki67 Level

In the discussion period, Dr. Hurvitz placed into context Ki67 levels, pathologic complete response, and event-free survival in patients with estrogen receptor–positive disease. Although Ki67 levels after neoadjuvant therapy do not predict for achievement of a pathologic complete response, this is not particularly relevant in patients with estrogen receptor–positive disease. The pivotal study by Cortazar et al showed that lack of a pathologic complete response did not portend a poor outcome in this subtype, likely because patients received years of subsequent endocrine therapy,2 she said.

On the other hand, a reduction in Ki67 level after 14 days is associated with improved event-free survival, according to a strong body of research. In addition, Ki67 levels after neoadjuvant therapy may serve as a guide to treatment: patients whose Ki67 levels do not change may benefit from chemotherapy.

Safety Profile

“Adverse events related to any treatment were fairly similar between the two treatment arms,” stated Dr. Hurvitz.

Treatment-related adverse events of any grade were recorded for 52.8% of the giredestrant arm vs 49.1% of the anastrozole arm. However, those related to endocrine therapy were lower in the giredestrant arm, 28.3% vs 38.2%, respectively, and there were no grade 3 or 4 serious toxicities related to the selective estrogen receptor degrader.

Adverse events of any grade related to palbociclib occurred in about 36% of each arm. About 14% of each arm required dose interruptions of palbociclib; adverse events leading to dose reductions of palbociclib were seen in 5.7% receiving giredestrant and 1.8% receiving anastrozole. No adverse events led to dose interruptions of the endocrine therapy.

The anastrozole arm experienced more arthralgias, decreased white blood cell counts, increased alanine aminotransferase, and pruritus, whereas patients taking giredestrant had more vomiting and bradycardia. However, just one of the three cases of bradycardia was believed to be related to giredestrant.

A phase III trial of giredestrant plus palbociclib vs letrozole plus palbociclib in metastatic breast cancer—persevERA Breast Cancer—and a phase III adjuvant trial investigator giredestrant—lidERA Breast Cancer—are ongoing. 

DISCLOSURE: Dr. Hurvitz has an immediate family member who holds stock or other ownership interests in Ideal Implant and ROMTech; has received institutional research funding from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, MacroGenics, Novartis, Pfizer, OBI Pharma, Pieris, Puma Biotechnology, Radius, Sanofi, Seattle Genetics/Seagen, Zymeworks, Phoenix Molecular Designs, and Samumed; and has been reimbursed for travel or accommodations by Lilly.


1. Hurvitz SA, Park YH, Bardia A, et al: Neoadjuvant giredestrant (GDC-9545) + palbociclib vs anastrozole + palbociclib in post-menopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer: Interim analysis of the randomized, open-label, phase II coopERA BC study. ESMO Congress 2021. Abstract LBA14. Presented September 20, 2021.

2. Cortazar P, Geyer CE Jr: Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 22:1441-1446, 2015.

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