evERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2– LA/mBC).

TPS1119 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane are the current approved second-line regimens. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations (m) driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1-mut status. While Phase I SERD combination data in the post-CDK4/6i setting are encouraging, there are no randomized combination data. Combining giredestrant and everolimus may improve outcomes after CDK4/6is and in pts with ESR1m tumors. Methods: evERA BC (NCT05306340), a Phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs. exemestane + everolimus in pts with ER+, HER2– LA/mBC who had previous treatment with a CDK4/6i and ET in the LA/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD), or exemestane (25 mg) + everolimus (10 mg) PO QD. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment. Eligibility: Female/male pts ≥ 18 years with ER+, HER2– LA/mBC and disease progression ≥ 6 months (mo) after initiating ET + CDK4/6i in the LA/mBC setting (and ≥ 4 mo on most recent ET, if ET + CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 mo of exposure to combination adjuvant ET (≥ 12 mo) + CDK4/6i (≥ 6 mo), and available blood sample for circulating tumor DNA central testing for ESR1m status. Men and pre-/perimenopausal women will receive a LHRH. Co-primary endpoints: Investigator-assessed progression-free survival (per RECIST v1.1) in the intent-to-treat and ESR1m populations. Secondary endpoints: Overall survival; objective response rate; duration of response; clinical benefit rate; pt-reported outcomes; safety; pharmacokinetics. Co-primary endpoint analyses will use a two-sided stratified log-rank test at an overall 0.05 significance level. An independent data monitoring committee will be in place for safety. Target enrollment is 320 pts, and this study is currently recruiting. Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340 .