Professor Wang Xiaojia: Learn from the past, and see how Giredestrant is changing the treatment landscape of HR-positive breast cancer

At present, new oral SERD drugs such as Giredestrant have become a hot spot
in clinical research.
Because after AI, fulvestrant is a very important choice in single-agent endocrine therapy, but intramuscular injection has certain limitations: first, injections on both buttocks will bring anxiety to patients and lead to poor compliance; Secondly, the real effective dose was not reached, the dosage was increased from 250 mg to 500 mg, and the patient's blood concentration was still relatively low, and the steady-state blood concentration could not be reached after 1 month of administration²
.
Therefore, new oral SERD drugs are expected to meet current clinical needs
.

Giredestrant (GDC-9545) is a highly potent non-steroidal oral SERD that, by binding strongly to ER, causes ER to be unable to activate transcription of targeted genes and promotes ER protein degradation, thereby more thoroughly blocking ER signaling and inhibiting tumor cell proliferation³
.
Preclinical studies have shown that Giredestrant has been exposed to 6 times as much as fulvestrant, and 30 mg can achieve near-complete ER binding (>90%), which fully demonstrates its complete antagonistic character and can act on ER mutations associated with drug resistance²⁻⁶
.
Giredestrant supports once-daily oral administration and, at a dose of 30 mg, is well tolerated by patients and has shown good clinical benefit
.

The CoopERA study⁷⁻⁹ and the acelERA study¹⁰ are two key studies
from Giredestrant.
coopERA is a randomized phase II study
using Giredestrant plus pibocicilil versus anastrozole plus perbociclib in the neoadjuvant treatment of ER+/HER2-untreated postmenopausal early stage breast cancer.
A total of 221 patients with ER+/HER2-untreated postmenopausal breast cancer with baseline ki67≥5%
were included in the study.
Patients 1:1 were randomized to the Giredestrant group versus the anastrozole group
.
The Giredestrant group received 2 weeks of Giredestrant monotherapy followed by 16 weeks of Giredestrant plus pibociclib neoadjuvant therapy; The anastrozole group received 2 weeks of neoadjuvant treatment with anastrozole followed by 16 weeks of neoadjuvant therapy
with prastrozole plus pipercillide.
The primary endpoint was change
from baseline in week 2 of the center's assessment.

This year, ASCO updated the final analysis data of coopERA BC⁸, showing that the inhibitory effect of Giredestrant on Ki67 observed at week 2 was greater than that of anastrozole (75% vs 67% of the geometric mean of Ki67 decline from baseline, respectively), with a P value of 0.
0433, which was statistically significant, and the study met the primary endpoint
.
The geometric mean of the decrease in Ki67 from baseline was maintained with surgery with the addition of pipebociclib (81 versus 74 percent).

The safety data were consistent with the known safety profile of Giredestrant, with similar
rates of adverse events (AEs) in both groups.
This is the first randomized controlled study to confirm that Giredestrant is superior to anastrozole
.

Results of the coopERA biomarker subgroup analysis were published at ESMO⁹ In multiple clinical subgroups, Giredestrant treatment significantly reduced Ki67 for 2 weeks compared with the anastrozole group, especially in clinically high-risk groups such as higher stages of AJCC (geometric mean of Ki67 percent decrease from baseline 74.
3 versus 61.
7 percent), clinical lymph node positive (79 versus 59.
3 percent), and PgR negative (60.
1 versus 39 percent) ) and other high-risk features in the tumor subgroup
.

Fig.
1 Results of Ki67 changes in week 2 of coopERA biomarker subgroup analysis

As expected, Giredestrant significantly reduced ER protein levels compared with anastrozole (-42 versus 32 percent), and PgR levels in the Giredestrant group showed a greater downward trend than in the anastrozole group (-48 versus -42 percent).

。 In addition, a stronger tendency was observed in tumors with high-risk features (G3, cN1+) to reduce ER pathway activity in Giredestrant compared with anastrozole (G3 subgroup: ER activity score change -0.
88 vs -0.
64; cN1+ subgroup: -0.
77 vs -0.
63), respectively).

These data provide a basis
for further evaluation of Giredestrant in the adjuvant phase of ER+ breast cancer.

Fig.
2 Changes in ER/PgR protein levels in week 2 of coopERA biomarker subgroup analysis

Fig.
3 Results of ER activity score changes in coopERA biomarker subgroup analysis

The acelERA study is a phase II study
comparing Giredestrant with physician-selected endocrine monotherapy in patients with previously treated ER+/HER2– locally advanced or metastatic breast cancer (LA/mBC).
A total of 303 patients with LA/mBC who had previously received first- or second-line systemic therapy were enrolled with investigator-assessed progression-free survival (PFS)
as the primary endpoint.
This year ESMO published the preliminary analysis results of the acelERA BC study¹⁰
.
Approximately 39% of patients had an ESR1 mutation at baseline; 71% of patients had previously received first-line therapy
.
Seventy-five percent of the patients in the control group received physician-selected endocrine monotherapy fulvestrant at a median follow-up of 7.
89 months, and the median PFS assessed by investigators in the Giredestrant group versus physician-selected endocrine monotherapy group was 5.
6 months and 5.
4 months, respectively, with an HR of 0.
81, although PFS did not reach statistical significance, but the value was slightly higher than that of the physician-selected endocrine monotherapy group
。 Moreover, the Giredestrant group had better benefits
in patients treated with CDK4/6 inhibitors (HR 0.
8), fulvestrant (HR 0.
65), and visceral disease (HR 0.
77).

Fig.
4 PFS results evaluated by investigators in the acelERA BC study

It is worth noting that in the ESR1 mutated population (AI-resistant population), the median PFS of the two groups was 5.
3 months and 3.
5 months, respectively, and the HR was 0.
60, which showed a significant numerical improvement
.
Furthermore, the secondary efficacy endpoints clinical benefit rate (CBR, 31.
8 versus 21.
1 percent) and objective response rate (ORR, 12.
6 versus 7.
2 percent) in the Giredestrant group were numerically superior to the physician-selected endocrine monotherapy group
.
In addition, in terms of safety, Giredestrant is well tolerated, with a safety profile comparable to that of the control group and consistent
with known endocrine therapy risks.
The incidence of grade 3/4 treatment-related adverse events (TRAE), severe AEs, and withdrawal due to AEs was balanced
between groups.
Overall, there is significant heterogeneity in advanced posterior HR+ breast cancer, while endocrine monotherapy efficacy is limited
.
Therefore, although the results of acelERA research results are not satisfactory, the efficacy is still observed to be prolonged, especially in the ESR1 mutation population, the efficacy trend is more obvious, and the safety is better, which provides a basis
for future research design.

Fig.
5 Secondary efficacy endpoint results of acelERA study

Yimaitong: The new oral SERD has revolutionized the treatment model of breast cancer, but the development of SERD drugs has not been smooth
.
Amcenestrant's Phase 2 AMEERA-3 clinical trial failed to reach the primary endpoint of improving ER+/HER2-mBC advanced second-line or multi-line PFS, and Elacetrian showed significant improvement in PFS in ER+/HER2-mBC second-line and above patients.