While lasfoxifene alone did not meet the primary end points that researchers set out for it, they did find that it improves responses in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations.
Investigators determined that the nonsteroidal selective estrogen receptor modulator (SERM) lasofoxifene elicited a benefit in objective response rate (ORR) and clinical benefit rate. However, lasofoxifene alone did not produce a statistically significant improvement in progression-free survival (PFS) vs fulvestrant (Faslodex) for patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer harboring ESR1 mutations, according to data from the phase 2 ELAINE 1 trial (NCT03781063).
Findings presented at the ESMO 2022 Congress showed that patients treated with lasofoxifene (n = 52) achieved a median PFS of 6.04 months (95% CI, 2.82-8.04) compared with 4.04 months (95% CI, 2.93-6.04) for patients who received fulvestrant (n = 51; HR, 0.699; 95% CI, 0.445-1.125; P = .138). The 6- and 12-month PFS rates in the lasofoxifene arm were 53.4% and 30.7%, respectively, vs 37.9% and 14.1%, respectively, in the fulvestrant arm (P = .138).
“Lasofoxifene did not statistically improve PFS, but we did see numerically superior outcomes in all of these primary and secondary areas, such as PFS and ORR,” lead study author Matthew P. Goetz, MD, a professor of oncology and pharmacology and a consultant in the Division of Medical Oncology in the Department of Oncology at Mayo Clinic, said in a presentation of the data.
ESR1 mutations in patients with ER-positive, HER2-negative breast cancer are associated with endocrine resistance, metastases, and poor prognosis. Selective estrogen degraders, such as fulvestrant, have displayed limited efficacy in this patient population.
Lasofoxifene is a third-generation oral SERM that improved tumor growth inhibition and metastases reduction vs fulvestrant in preclinical models. Additionally, the combination of lasofoxifene and abemaciclib (Verzenio) produced an ORR of 50% and a median PFS of 13.9 months in patients ER-positive, HER2-negative metastatic breast cancer harboring ESR1 mutations following treatment with a CDK4/6 inhibitor in the phase 2 ELAINE 2 trial (NCT04432454).
ELAINE 1 evaluated lasofoxifene monotherapy vs fulvestrant in patients with ESR1-mutated, ER-positive/HER2-negative metastatic breast cancer who progressed on prior aromatase inhibitors (AIs) plus a CDK4/6 inhibitor.
The trial randomly assigned patients to 5 mg of oral lasofoxifene 500 mg of fulvestrant as an intramuscular injection on days 1, 15, and 29, then every 4 weeks thereafter. Treatment continued until progression, death, unacceptable toxicity, or withdrawal.
The primary end point of the trial was PFS. Secondary end points included ORR, clinical benefit rate, overall survival, and safety.
The median age in the lasofoxifene arm and the fulvestrant arm was 61.6 years (range, 33-84) and 60.1 years (range, 38-82), respectively. The majority of patients had measurable disease (73.1% and 64.7% in the lasofoxifene and fulvestrant arms, respectively) and visceral disease (67.3% and 64.7%). Rates of prior chemotherapy in the metastatic setting were 5.8% and 5.9% in the lasofoxifene and fulvestrant groups, respectively.
All patients received prior treatment with an AI and CDK4/6 inhibitor, and the median duration of treatment with an AI and CDK4/6 inhibitor was 2.5 years and 2.2 years in the lasofoxifene and fulvestrant arms, respectively. All patients had an ESR1 mutation, and ESR1 Y537S mutations were reported in 40% and 47% of patients in the lasofoxifene and fulvestrant groups, respectively.
At data cutoff, 4 patients in the lasofoxifene arm were ongoing treatment, compared with 2 in the fulvestrant arm. Forty-three patients in each arm stopped treatment due to disease progression.
Additional data showed lasofoxifene elicited an ORR of 13.2% compared with 2.9% for fulvestrant (P = .12). In the lasofoxifene arm, 1 patient achieved a complete response with a duration of 18 months. Four patients had partial responses (PRs) with a median duration of 13.75 months. One patient in the fulvestrant arm achieved a PR with a duration of 16 months.
The clinical benefit rate after 24 weeks in the lasofoxifene group was 36.5% vs 21.6% in the fulvestrant group (P = .12).
An exploratory circulating tumor DNA (ctDNA) analysis assessed the baseline and 8-week ctDNA samples of 61 patients for ESR1-mutant allele fraction. The median relative change for all variants in the lasofoxifene arm was –87.1% compared with –14.7% in the fulvestrant arm. In patients with ESR1 Y537S mutations, the median mutant allele fraction change was –89% in the lasofoxifene arm and –82% in the fulvestrant arm.
Regarding safety, most adverse effects (AEs) were grade 1/2 and no thrombotic AEs were reported. The most common treatment-emergent AEs of any grade were nausea (27.5% and 18.8% in the lasofoxifene and fulvestrant arms, respectively), fatigue (23.5% and 37.5%), arthralgia (21.6% and 22.9%), hot flush (21.6% and 10.4%), constipation (15.7% and 12.5%), dizziness (15.7% and 4.2%), hypertension (15.7% and 14.6%), and cough (15.7% and 10.4%).
One patient in the lasofoxifene arm discontinued treatment due to AEs.
Investigators are planning a phase 3 trial to evaluate the combination of lasofoxifene and abemaciclib, based on findings from ELAINE 1 and ELAINE 2. “In terms of monotherapy, a larger trial is going to be needed to determine if lasofoxifene can be an alternative to fulvestrant,” Goetz concluded.
Goetz MP, Plourde P, Stover DG, et al. 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. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089