Lasofoxifene shows promise for women with ESR1-mutated mBC

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Published: 11 Sep 2022
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Prof Hope Rugo - UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA

Prof Hope Rugo speaks to ecancer, at ESMO 2022, about ELAINE 1 a randomised trial of lasofoxifene versus fulvestrant in a post-CDK4/6 inhibitors second-line setting for women with locally advanced metastatic ER+/HER2- breast cancer (mBC), an oestrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 inhibitors. 

ELAINE 1 is the first clinical trial comparing lasofoxifene with fulvestrant in ESR1- mutated mBC patients with progression on CDK4/6 inhibitors demonstrating activity of a novel SERM in this setting. 

The results showed all clinical outcomes numerically favoured lasofoxifene versus fulvestrant in this signal-seeking study. Lasofoxifene may be a new treatment option following endocrine/CDK4/6 inhibitor therapies if efficacy is confirmed in a larger, adequately powered clinical study. 

A phase 3 combination study of lasofoxifene and abemaciclib is planned based on encouraging efficacy/safety in ELAINE 2.

ELAINE 1 is a randomised phase II trial that was presented by my colleague, Matt Goetz, but we
participated in the trial. It’s a really interesting agent: lasofoxifene is a novel SERM. It seems to be
very effective and particularly effective in patients who have ESR1 mutations, so really fascinating.
What we did in that trial was randomise patients to receive lasofoxifene or fulvestrant, so they can’t
have received prior fulvestrant. What we saw was a numeric improvement in the progression free
survival and response but the endpoint was PFS, in terms of statistical significance it wasn’t
significant. But the difference was really quite nice to see, going from 4+ months to 6+ months, so
really encouraging.

The important thing about ELAINE 1 was it just wasn’t any patient; because lasofoxifene has this
activity that had been seen in ESR1 mutant disease we narrowed the eligibility to patients who had
ESR1 mutations. So then they looked at specifically this ESR1 mutation that has been associated
with resistance to fulvestrant and in that group of patients we looked at ctDNA to see what happened
to ESR1, so cell-free DNA. People have shown that when you effectively treat a cancer that the ESR1
goes down in cell-free DNA, we’ve seen this with a number of markers, even PIK3CA mutations. But
when we looked at that resistance, the ESR1 mutation, now we understand there’s not just one, there
are lots of them, the ESR1 mutation associated with fulvestrant resistance went way down, like 80%,
in patients who received lasofoxifene and it actually went up in the majority of patients who received
fulvestrant, so fascinating data.

There is also an ELAINE 2 trial that was presented at ASCO and in that trial abemaciclib was
combined with lasofoxifene and saw very nice responses. So the next planned trial is to look at
lasofoxifene and abemaciclib versus fulvestrant and abemaciclib in a more registration type trial.
Of course when we’re thinking about new agents, we always want to think about toxicity and
lasofoxifene is very well tolerated. In this phase II trial we didn’t see thrombotic events. With
abemaciclib we’ll have to watch that very carefully because we know abemaciclib is already
associated with some thrombosis. But very, very interesting data.