Neoadjuvant giredestrant (GDC-9545) plus palbociclib (P) versus anastrozole (A) plus P in postmenopausal women with estrogen receptor–positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): Final analysis of the randomized, open-label, international phase 2 coopERA BC study.

Abstract

589 Background: Endocrine therapy (ET) is the therapeutic mainstay for ER+ BC. Giredestrant is a highly potent, nonsteroidal, oral, selective ER antagonist and degrader (SERD) which has demonstrated robust ER occupancy, is well tolerated, and has previously shown encouraging antitumor activity as monotherapy and in combination with P in metastatic BC. coopERA BC (NCT04436744) evaluated giredestrant in eBC and met its primary endpoint, highlighting superior Ki67 suppression with single-agent giredestrant vs A at Week 2. Giredestrant was well tolerated. Here, we report the final analysis. Methods: Eligible patients (pts) with measurable ER+/HER2– untreated eBC and baseline Ki67 score ≥5% (202 planned) were randomized 1:1 to receive, on Days 1–14 of a neoadjuvant window-of-opportunity phase, 30 mg oral daily (PO QD) giredestrant or 1 mg PO QD A followed by a 16-week neoadjuvant phase of QD giredestrant or A for four 28-day cycles with 125 mg PO P on Days 1–21. Randomization was stratified by tumor size, baseline Ki67 score, and progesterone receptor status. Endpoints assessed here included Ki67 suppression from baseline to surgery, complete cell cycle arrest (CCCA; Ki67 ≤2.7%) at surgery, objective response rate (ORR), and safety. Results: At final analysis (cutoff: Nov 24, 2021), 112 and 109 pts were randomized to the giredestrant and A arms, respectively (median age: 62 years each; stage I/IIa disease: 60% vs 54%). Consistent with the primary analysis, greater suppression of Ki67 was observed at surgery with giredestrant + P (–81% [95% confidence interval (CI): –86%, –75%]) vs A + P (–74% [95% CI: –80%, –67%]). Similarly, greater CCCA was achieved at surgery with giredestrant + P (20%) vs A + P (14%). ORR was similar between the two arms (giredestrant + P: 50% [95% CI: 40%, 60%]; A + P: 49% [95% CI: 39%, 59%]). ET-related adverse events (AEs) were non-serious and occurred at similar rates between the two arms. Related Grade ≥3 AE rates were also similar at 6% each. Interruption/withdrawal of ET due to AEs was low and similar for both arms. Conclusions: In this final analysis of coopERA BC, the greater suppression of Ki67 with giredestrant vs A observed at Week 2 in the primary analysis was maintained at surgery, and safety data remained consistent with the known safety profile of giredestrant. coopERA BC is the first randomized study to show superior antiproliferative activity of an oral SERD (giredestrant) over an aromatase inhibitor (A) in ER+/HER2– eBC; studies are ongoing to further assess giredestrant’s clinical benefit. Clinical trial information: NCT04436744.

The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options

“…acelERA is a randomized phase II trial of giredestrant vs fulvestrant or aromatase inhibitor that failed to meet its primary endpoint of superior PFS for the study drug [79], although subgroup analysis of patients with baseline ESR1 mutations appeared to show promising effects. Giredestrant did outperform anastrozole in reducing Ki67 expression and inducing complete cell cycle arrest when used as neoadjuvant therapy for previously untreated patients from the coopERA study in postmenopausal women with hormone receptor-positive, HER2 − early breast cancer [80]. Giredestrant is currently explored as first-line therapy for advanced breast cancer and early-stage breast cancer.…”

“…For tumors that are hormonal therapy naïve or first-line therapy, oral SERDs plus CDK4/6 inhibitors are being compared with AIs plus CDK4/6 inhibitors as in AMEERA-5 [87] (amcenestrant), SERENA 4 [88](camizestrant), or with physicians' choice plus CDK4/6 inhibitors as in acelERA Breast Cancer [78] (giredestrant) and in tumors with ESR1 mutation, as in SERENA 6 [89] (camizestrant). In the neoadjuvant setting, oral SERDs are being explored in locally advanced HR + /HER2 − stage III breast cancer against AIs alone as in AMEERA-4 [90] (amcenestrant) or in combination with CDK4/6 inhibitors as in coopERA BC study [80] (giredestrant). Similarly, in the adjuvant treatment of early breast cancer, oral SERDs are being studied against AIs or physicians' choice as in the Lidera Breast Cancer Study [91] (giredestrant) or tamoxifen as in AMEERA-6 [92] (amcenestrant) in HR + /HER2 − stages I-II early breast cancers.…”

Accelerating drug development in breast cancer: New frontiers for ER inhibition

“…The coopERA trial is a randomized, phase II neoadjuvant trial of giredestrant versus anastrozole, with the addition of palbociclib in both arms after 14 days of treatment. The final analysis on 201 evaluable patients on the lead-in phase of the study (without palbociclib) has shown a statistically significant reduction in Ki67 after 14 days of treatment with giredestrant compared to AI (relative reduction in geometric Ki67 of − 75% vs − 67%, respectively) [75]. However, giredestrant combined with palbociclib did not show an improvement in terms of pCR rate compared to the control arm.…”

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

“… 76 At the end of the neoadjuvant combination treatment phase, geometric mean relative reduction in Ki67 was again superior in the giredestrant arm at −81% compared with −74%, but there was no difference in the ORR nor pathological complete response rate between the trial arms. 77 …”

“…76 At the end of the neoadjuvant combination treatment phase, geometric mean relative reduction in Ki67 was again superior in the giredestrant arm at −81% compared with −74%, but there was no difference in the ORR nor pathological complete response rate between the trial arms. 77 In the AMEERA-4 trial, 105 patients with ER positive, HER2 negative early breast cancer with a primary tumor ≥ 1.0 cm and Ki67 ≥ 15% were randomized 1:1:1 to amcenestrant 400 mg daily, amcenestrant 200 mg daily, or letrozole 2.5 mg daily for 2 weeks before surgery. 78 No formal statistical comparisons were performed as the study had closed early due to slow trial enrollment.…”