Greater Ki67 Suppression Achieved With Giredestrant Compared With Anastrozole in ER+/HER2– Early Breast Cancer

Results from an interim analysis of the phase 2 coopERA Breast Cancer trial (NCT04436744) of patients with estrogen receptor (ER)–positive, HER2-negative early breast cancer indicated that giredestrant led to greater relative reduction in Ki67 score from baseline to week 2 of a window of opportunity phase vs anastrozole, according to data presented at the 2021 European Society of Medical Oncology Congress.¹

Results showed that the centrally assessed geometric mean relative Ki67 reduction from baseline to week 2 was -80% (95% CI, -85% to -72%) with giredestrant vs -67% (95% CI, -75% to -56%) with anastrozole (P = .0222). Additionally, more tumors displayed a complete cell cycle arrest (CCCA) with giredestrant compared with anastrozole, at 25.0% (n = 11/44) and 5.1% (n = 2/39), respectively. Additionally, consistent Ki67 suppression was observed in patients with baseline Ki67 of 20% or greater and less than 20%.

“This is the first randomized study showing activity of an oral selective estrogen receptor degrader [SERD] over an aromatase inhibitor, and the study will continue to primary analysis,” Sara Hurvitz, MD, 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 associate professor of medicine in the Division of Hematology/Oncology, at the David Geffen School of Medicine at UCLA, said during a presentation on the data.

Targeting ER activity and/or estrogen synthesis is the mainstay of therapy for patients with ER-positive breast cancer, but many patients will relapse or experience early treatment resistance.² Ki67 is a biomarker of proliferation and decreases in this marker have been linked with better long-term efficacy outcomes in early-stage breast cancer.^3-6

Giredestrant is a highly potent, non-steroidal, oral SERD that has been shown to be well tolerated, and to have encouraging antitumor activity when used as a monotherapy and in combination with the CDK4/6 inhibitor palbociclib (Ibrance) in metastatic breast cancer.^7,8 A 30-mg standardized dose has been selected for the examination of giredestrant as a single agent and in combination with palbociclib.

The neoadjuvant phase 2 coopERA enrolled postmenopausal patients with ER-positive, HER2-negative, untreated breast cancer with a baseline Ki67 score of 5% or more, and a tumor that was at least 1.5 cm at the time of presentation. Patients had to have baseline tumor tissue available.

A total of 202 patients were randomized 1:1 to receive either oral giredestrant monotherapy at a daily dose of 30 mg, or oral anastrozole monotherapy at a daily dose of 1 mg, during a 2-week window of opportunity phase. Patients then went on to receive 16 cycles (28 days each) of either giredestrant (days 1-28) or anastrozole (days 1-28) at the same dose, combined with oral palbociclib at a daily dose of 125 mg (days 1-21).

The primary end point 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 end points included CCCA, which was defined as having a Ki67 score of 2.7% or less at week 2, as well as safety.

“The prespecified critical P value for statistical significance for this interim analysis was .01029,” Hurvitz noted.

Moreover, patients were stratified by T status (cT1c-cT2 vs cT3-cT4a-c), Ki67 score (less than 20% vs 20% or more), and progesterone receptor (PgR) status (positive vs negative).

Ultimately, 109 patients were randomized to either the giredestrant arm (n = 54; intent-to-treat [ITT] population) or the anastrozole arm (n = 55; ITT population). The safety-evaluable population, defined as all patients who received any amount of study treatment, included 53 patients on the giredestrant arm and 55 on the anastrozole arm. The efficacy-evaluable population, defined as all ITT patients with an available, centrally confirmed Ki67 score at baseline and week 2, included 44 patients on the giredestrant arm and 39 on the anastrozole arm.

Baseline characteristics were similar across the 2 study arms. Patients in the giredestrant arm had a mean age of 64.6 years (range, 44.0-83.0) vs 62.3 years (range, 42.0-81.0) in the anastrozole arm, and the PgR positivity status for each group was 88.9% and 83.6%, respectively. Additionally, most patients in both arms had stage IIA disease at diagnosis (45.3% vs 38.2%), had a nodal status of N0 (55.6% vs 49.1%), and had a tumor status of T2 (64.8% vs 61.8%).

Most patients in each study arm had a mean baseline Ki67 of 20% or more (n = 34, each). Ten patients in the giredestrant arm and 5 patients in the anastrozole arm had a mean baseline Ki67 of less than 20%. Across both subsets of patients, giredestrant was associated with a higher mean reduction in Ki67 score, at -83% (95% CI, -88% to -75%) in those with baseline Ki67 of 20% or more vs 71% (95% CI, -78% to -60%) with anastrozole, and -65% (95% CI, -81% to -34%) in those with baseline Ki67 of less than 20% vs -24% (95% CI, -65% to 67%) with anastrozole.

In terms of safety, no grade 3/4 serious adverse effects (SAEs) reported were related to treatment with giredestrant. Overall, 52.8% of patients experienced any-grade AEs that were related to treatment in the giredestrant arm vs 49.1% in the anastrozole arm, and the rate of any-grade AEs that were related to endocrine therapy were 28.3% and 38.2%, respectively.

AEs leading to a dose interruption of palbociclib were needed in 13.2% of patients on the giredestrant arm vs 14.5% of those on the anastrozole arm, and the rates of AEs leading to dose reduction of palbociclib were 5.7% and 1.8%, respectively. No AEs resulted in a dose interruption of endocrine therapy in either arm.

Frequently reported AEs in the investigative and control arms, respectively, included arthralgia (5.7% vs 10.9%), decreased white blood cell count (3.8% vs 9.1%), increased alanine aminotransferase (0% vs 7.3%), pruritis (0% vs 7.3%), bradycardia (5.7% vs 0%), and vomiting (5.7% vs 0%).

References

1. Hurvitz S, Park YH, Bardia A, et al. Neoadjuvant giredestrant (GDC-9545) + palbociclib (palbo) vs anastrozole (A) + palbo in post-menopausal women with oestrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): Interim analysis of the randomised, open-label, phase 2 coopERA BC study. Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021; Virtual. LBA14.
2. Jhaveri K, Winer EP, Lim E, et al. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer. Cancer Res. 2020;80(4):PD7-05. doi:10.1158/1538-7445.SABCS19-PD7-05
3. Dowsett M, Smith IE, Ebbs SR, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11(2):951s-958s. https://bit.ly/39mYEJZ
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6. Anderson H, Hills M, Zabalgo L, et al. Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer. Ann Oncol. 2011;22(8):1770-1776. doi:10.1093/annonc/mdq700
7. Lim E, Jhaveri KL, Perez-Fidalgo JA, et al. A phase Ib study to evaluate the oral selective estrogen receptor degrader GDC-9545 alone or combined with palbociclib in metastatic ER-positive HER2-negative breast cancer. J Clin Oncol. 2020;38(15):1023. doi:10.1200/JCO.2020.38.15_suppl.1023
8. Jhaveri KL, Boni V, Sohn J, et al. Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC). J Clin Oncol. 2021;39(15):1017. doi:10.1200/JCO.2021.39.15_suppl.1017