LBA20 - Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors

Background

Acquired ESR1 mutations cause endocrine resistance, driving metastasis and poor prognosis in patients with ER+/HER2- mBC. A phase 2 trial of LAS plus abemaciclib (ELAINE 2) showed efficacy in heavily pretreated patients with ESR1-mutated mBC post-CDK4/6i (ASCO 2022). Here we describe ELAINE 1, a randomized trial of LAS vs Fulv in a post-CDK4/6i second-line setting.

Methods

Women with ER+/HER2-/ESR1-mutated mBC and progression on prior (≥12 mos) AI plus CDK4/6i (n=103) were randomized to oral LAS 5 mg (n=52) daily or IM Fulv 500 mg (n=51) days 1, 15, and 29, then every 4 weeks, until disease progression or severe toxicity. Imaging occurred every 2 mos (or if clinically indicated). Primary endpoint was progression-free survival (PFS).

Results

Mean age was 60.8 yr (33-84); 83% were white, 66% had visceral disease, 71% (n=73) had measurable disease. For LAS vs Fulv, median PFS was 6.04 mos (95% CI, 2.82–8.04) vs 4.04 mos (95% CI, 2.93–6.04), P=0.138 (HR, 0.699 [95% CI, 0.445–1.125]); PFS at 12 mos was 30.7% vs 14.1%; clinical benefit rate was 36.5% vs 21.6%, P=0.12. Objective response rate for LAS vs Fulv was 13.2% vs 2.9%, P=0.12, with 1 complete response (60-week duration) and 4 partial responses (PR) in the LAS arm versus 1 PR in the Fulv arm. PFS was numerically and consistently greater with LAS vs Fulv when visceral metastasis and/or Y537S ESR1 mutation subgroups were analyzed. Clearance of ctDNA also favored LAS over Fulv. Most common adverse events were fatigue, nausea, arthralgias, and hot flushes; most were Grade 1/2. No thrombotic events occurred.

Conclusions

ELAINE 1 is the first clinical trial comparing LAS with Fulv in ESR1-mutated mBC patients with progression on CDK4/6i and demonstrating activity of a novel SERM in this setting. All clinical outcomes numerically favored LAS vs Fulv in this signal-seeking study. LAS may be a new treatment option following endocrine/CDK4/6i therapies if efficacy is confirmed in a larger, adequately powered clinical study. A phase 3 combination study of LAS and abemaciclib is planned based on encouraging efficacy/safety in ELAINE 2.

Clinical trial identification

NCT03781063.

Editorial acknowledgement

Medical writing assistance was provided by Kathleen Ohleth, PhD of Precise Publications, LLC.

Legal entity responsible for the study

Sermonix Pharmaceuticals.

Funding

Sermonix Pharmaceuticals.

Disclosure

M.P. Goetz: Financial Interests, Institutional, Advisory Role: Mayo Clinic, Biovica, Biotheranostics, Blueprint Medicines, Eagle Pharmaceuticals, Lily, Novartis, Pfizer, Sanofi Genzyme, Sermonix; Financial Interests, Personal, Invited Speaker: Research to Practice, Clinical Education Alliance, Medscape, Total Health Conferenceing, Curio Science; Financial Interests, Institutional, Research Grant: Mayo Clinic, Pfizer, Sermonix. P. Plourde: Financial Interests, Personal, Full or part-time Employment: Sermonix; Financial Interests, Personal, Stocks/Shares: Sermonix. D.G. Stover: Financial Interests, Personal, Advisory Board: Novartis. N. Bagegni: Financial Interests, Institutional, Research Grant: Ambrx Inc, AstraZeneca Pharmaceuticals LP, Biovica International AB, Daiichi Sankyo, Novartis, Pfizer, Sarah Cannon Development Innovations LLC, Seattle Genetics, Sermonix, Xcovery Hholdings Company LLC. G.A. Vidal: Financial Interests, Personal and Institutional, Advisory Role: Roche/Genetech, Novartis, Eli-Lilly, Gilead, Puma, Pfizer, AstraZeneca, Biotheranautics, Daiichi Sankyo, Concerto Al; Financial Interests, Personal, Training: Eli-Lilly; Financial Interests, Institutional, Research Grant: Roche/Genetech, Puma, Celcuity, Merck, BMS, Eli-Lilly, AstraZeneca, Pfizer, Gilead, GSK; Financial Interests, Personal, Ownership Interest: Oncodisc. A. Brufsky: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, SeaGen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma; Financial Interests, Institutional, Research Grant: Agendia, AstraZeneca. H.S. Rugo: Financial Interests, Institutional, Research Grant: Pfizer, Merck, Novartis, Lilly, Roche, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala, Astellas, Gilead; Financial Interests, Personal, Other, Honoraria: Puma, Samsung, NAPO. D.J. Portman: Financial Interests, Personal, Full or part-time Employment: Sermonix; Financial Interests, Personal, Stocks/Shares: Sermonix. E. Gal-Yam: Financial Interests, Personal, Other, Honoraria: Eli-Lilly, Novartis, Pfizer, Roche, AstraZeneca, MSD.