CoopERA Results Show Benefits of Giredestrant in ER+/HER2– Early Breast Cancer

Giredestrant (GDC-9545), an investigational next generation oral selective estrogen receptor (ER) degrader (SERD), reduced Ki67 score more than anastrozole in patients with ER-positive, HER2-negative early breast cancer, according to Sara Hurvitz, MD, who presented interim data from the phase 2 coopERA Breast Cancer trial (NCT04436744) during the ESMO Oncology Congress 2021. She added that there is a growing body of evidence supporting giredestrant in this patient population.

Patients treated with giredestrant experienced a greater decline in Ki67 score from baseline to week 2 compared with for those who received anastrozole (Arimidex; -80% vs -67%; P = .0222). Additionally, more tumors displayed a complete cell cycle arrest (CCCA) with giredestrant compared with anastrozole, at 25.0% (n = 11/44) vs 5.1% (n = 2/39). Investigators also observed consistent Ki67 suppression in patients with baseline Ki67 scores of 20% or greater and less than 20%.

“The take home [here] is that this study is the first analysis in humans [with] an oral SERD compared with an aromatase inhibitor. The data provides proof of concept that the oral SERD giredestrant is having more of a biological impact in terms of Ki67 reduction compared with anastrozole at 2 weeks,” Hurvitz said.

In an interview with OncLive^®, Hurvitz, director of the Breast Cancer Clinical Research Program, co-director of the Santa Monica 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, discussed the coopERA study and how these data, along with findings from other clinical trials, could lead to significant changes in treatment for patients with ER-positive/HER2-negative breast cancer.

OncLive^®: Could you speak to the rationale for this study?

Hurvitz: Giredestrant is an oral estrogen receptor downregulator that’s being evaluated for ER-positive breast cancer. We have the use of 1 ER downregulator, fulvestrant [Faslodex], for metastatic ER-positive breast cancer, which appears to be better than single agent aromatase inhibitors [AI] in the metastatic setting. However, it needs to be delivered through an intramuscular injection [because] its oral bioavailability is too low, which is not convenient for patients. [Therefore], a SERD like giredestrant is being developed, and [has] shown early evidence of safety and efficacy in the metastatic setting. It's also fairly potent. We wanted to evaluate the biological activity of this drug in a clinical trial that would compare it to the biological activity of anastrozole. This would be the first clinical trial pairing an oral SERD like this to an AI to report out.

Can you explain the study’s design?

The coopERA clinical trial was a window of opportunity and neoadjuvant clinical trial in which patients who had breast cancer that was at least 1.5 cm in size and postmenopausal ER-positive/HER2-negative breast cancer were randomly assigned 1 to 1 to receive either 2 weeks of single agent giredestrant or 2 weeks of single agent anastrozole, with a biopsy prior to starting any therapy and a biopsy after 2 weeks of therapy. All patients then went on to receive either giredestrant or anastrozole in combination with palbociclib [Ibrance] for several months prior to going to surgery.

The primary endpoint of our trial was to measure whether there was a significant change in Ki67 [score], which is a marker of proliferation, from day 1 to 14 in either treatment arm. We know from other clinical trials [that] a significant drop in Ki67 from baseline to week 2 following endocrine therapy is associated with an improvement in event-free survival [and] may be a good surrogate marker for long-term outcomes. This study was designed to measure the biological activity in terms of inhibition of proliferation, comparing giredestrant to anastrozole..

What did you learn about giredestrant in this patient population?

A total of 83 patients were included in the interim analysis. There was a relative Ki67 reduction that was greater in the giredestrant arm compared with the anastrozole arm. The relative reduction at week 2 from baseline was a drop of 80% in the giredestrant arm compared with 67% in the anastrozole arm. Moreover, there was a greater incidence of CCCA associated with giredestrant, with 25% of patients’ tumors having complete cell cycle arrest, which is defined as a Ki67 drop down to 2.7% or lower. That compared favorably to a 5.1% complete cell cycle arrest in the anastrozole arm.

Did you observe any new safety signals?

The safety of giredestrant appears to be similar to that which was reported from the phase 1 metastatic setting and there were no new safety signals. It was interesting that there were no grade 3/4 adverse events noted with either giredestrant or anastrozole that [were] related to the endocrine therapy component. There were a few cases of bradycardia in the giredestrant arm, however, only 1 was related to the giredestrant and they were low-grade events. There were higher rates of arthralgia in the anastrozole arm, which is interesting to me since so many patients must contend with musculoskeletal side effects with the aromatase inhibitors.

Now what were the key takeaways from this study?

The data are immature—we’re still waiting for more patients to be enrolled. Additionally, we didn’t meet our level of statistical significance for the interim analysis, but we are hoping to do so at the time of reporting of our primary analysis hopefully in the next several months. These data are not practice changing immediately, but they do provide support for the current ongoing enrolling phase 3 clinical trials looking at adjuvant giredestrant and the LidERA study [NCT04961996] and the use of giredestrant in combination with palbociclib in the metastatic setting in the persevERA study [NCT04546009].

Was there any research presented at ESMO that you were particularly excited about?

Everyone is buzzing about the data from DESTINY-Breast03 [NCT03529110] with Fam-trastuzumab deruxtecan-nxki [T-DXd, Enhertu] compared with trastuzumab emtansine [T-DM1; Kadcyla] showing phenomenal improvement in progression free survival with T-DXd, as well as a really high objective response rate in this second line setting and greater. We're all very excited and I think these data are going to be practice changing.

The other study I would highlight is the phase 3 MONALEESA-2 trial [NCT01958021], in which the overall survival benefits of ribociclib [Kisqali] combined with anastrozole in the first-line setting for metastatic HR-positive breast cancer was shown to be significantly improved. This is the first study in the frontline of a CDK4/6 inhibitor combined with an AI to show a significant survival benefit in postmenopausal patients.

Reference

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 II coopERA BC study. Ann Oncol. 2021;32(suppl_5): S1283-S1346. 10.1016/annonc/annonc741.