ELAINE-3 Trial Sets Out to Confirm Clinical Benefit of Lasofoxifene/Abemaciclib in ESR1-Mutant, ER+ Breast Cancer

Seth A. Wander, MD, PhD

An ongoing evaluation of the selective estrogen receptor modulator (SERM) lasofoxifene plus abemaciclib (Verzenio) in the phase 3 ELAINE-3 trial (NCT05696626) may provide further insight into the efficacy of this novel combination for patients with ESR1-mutated, estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer who progressed on prior endocrine therapy and CDK4/6 inhibition, according to Seth A. Wander, MD, PhD.

Previously reported data from the phase 2 ELAINE-1 (NCT03781063) and ELAINE-2 (NCT04432454) trials in this patient population have demonstrated promising signals of clinical benefit with lasofoxifene. In ELAINE-1, lasofoxifene monotherapy produced a notable numerical improvement in median progression-free survival (PFS) from 3.7 months with fulvestrant (Faslodex) alone to 5.6 months (P = .138).1 Findings from ELAINE-2 showed that the combination of lasofoxifene plus abemaciclib was well tolerated and produced clinically meaningful efficacy ESR1-mutant patients, with a median PFS of 13 months and an overall response rate of 56%.^1,2

The ELAINE-3 trial was designed to validate these efficacy signals for lasofoxifene plus abemaciclib in a larger, randomized population. The combination will be compared with standard fulvestrant plus abemaciclib. The global, multicenter study is currently recruiting patients across 17 study sites.²

“The ELAINE-3 trial will build upon [the current] treatment landscape by showing us the benefit [conferred with] abemaciclib plus a next-generation anti-estrogen agent,” said Wander, who is an assistant professor of medicine at Harvard Medical School and a clinical assistant in medicine at Massachusetts General Hospital, both in Boston. “[It will hopefully] provide a wealth of new clinical data, as well as opportunities for translational analysis.”

In an interview with OncLive®, Wander expanded on key findings with lasofoxifene from ELAINE-1 and ELAINE-2 that supported the initiation of the ELAINE-3 trial, contextualized these results within the broader second- and third-line settings, and explained how ELAINE-3 may impact other trials attempting to improve upon standard anti-estrogen and CDK4/6 inhibitor therapy.

OncLive: What is the mechanism of action of lasofoxifene, and why is it an intriguing agent to combine with abemaciclib for patients with ESR1-mutated, ER-positive, HER2-negative breast cancer?

Wander: One of the most important areas of research across all ER-positive metastatic breast cancer today is the development of next-generation anti-estrogen therapies for patients who have developed resistance to currently available treatments. Lasofoxifene is an exciting molecule. It’s a next-generation SERM in the same family as tamoxifen [Soltamox], which we’ve had many decades of experience with. We have a long history of safety experienced with lasofoxifene, because it had previously been in development for indications outside of breast cancer. More recently, it has been under active development in phase 1, 2, and now phase 3 studies for patients with treatment-refractory hormone receptor–positive metastatic disease. It’s shown significant activity, both as monotherapy and now in combination with abemaciclib for patients who have developed resistance to standard anti-estrogens and standard CDK 4/6 inhibitors.

Could you elaborate on the patient population enrolled onto the ELAINE-2 trial?

The ELAINE-2 study was a single-arm, phase 2 study combining lasofoxifene with the CDK4/6 inhibitor abemaciclib. Here we were looking at patients that had previously progressed on an aromatase inhibitor [AI], typically with prior CDK4/6 inhibitors such as palbociclib [Ibrance] or ribociclib [Kisqali]. This was in patients with ER-positive, HER2-negative metastatic breast cancer that had progressed on prior endocrine therapy and a CDK4/6 inhibitor and had to have an ESR1 mutation.

Could you summarize the ELAINE-1 and ELAINE-2 data that supported the continued investigation of lasofoxifene in ELAINE-3?

We have developed a large body of work with lasofoxifene over the last couple of years. The ELAINE-1 study was an earlier effort looking at lasofoxifene monotherapy compared with fulvestrant in ESR1-mutant, ER-positive metastatic breast cancer that had prior progression on an AI with a CDK4/6 inhibitor. Lasofoxifene demonstrated meaningful amounts of clinical benefit in terms of PFS improvement, clinical benefit rate [CBR], and response rates. [However], based on you know, sample size, [these data] didn’t quite reach statistical significance.

ELAINE-2 was a phase 2, single-arm study looking at lasofoxifene plus abemaciclib. The study showed an impressive median PFS of 56 weeks, and a CBR over 65%. These estimates of median PFS and CBR exceeded what we might expect based on historical data from the [phase 2] MAINTAIN study [NCT02632045], as well as some retrospective data we’ve generated for abemaciclib after prior palbociclib progression. In the ELAINE-3 study, we’ll be moving all these data forward into the phase 3 setting.

Could you expand on the trial design and inclusion criteria for the ELAINE-3 study?

ELAINE-3 is an open label, randomized, multicenter study looking at lasofoxifene with abemaciclib as compared with fulvestrant and abemaciclib. Patients will be randomly assigned 1:1 [to these regimens], and this will be an international study. These are patients with ER-positive, HER2-negative metastatic disease. They had to progress on a prior AI with either palbociclib or ribociclib. As with prior efforts, this will be limited to the ESR1-mutant population, and the target sample size will be about 400 patients. This large, prospective randomized phase 3 study will hopefully give us a little bit more insight into the true benefit of lasofoxifene with abemaciclib in this post-AI and post-CDK inhibitor population. The study has just activated, and we’re in the process of screening and enrolling the first patients, with new sites coming online.

How has the current therapeutic landscape in ER–positive metastatic breast cancer evolved in the second-line setting and beyond, and how might ELAINE-3 fit into this paradigm?

We’ve had multiple new primarily biomarker-based approvals over the last couple of years. Right now, the widely utilized standard first-line treatment would include the combination of an AI with a CDK 4/6 inhibitor. In the United States and abroad, there’s been more of a trend toward using ribociclib based on emerging survival data from these first-line studies. If a patient receives an AI with ribociclib in the first-line metastatic setting and progresses, it’s becoming increasingly complicated [to select between therapies with] multiple parallel approvals in the second- and third-line setting.

For patients with PIK3CA-mutant disease, we have alpelisib [Piqray] with fulvestrant based on the phase 3 SOLAR-1 study [NCT02437318]. More recently, we received an approval for the AKT inhibitor capivasertib [Truqap] for patients with either PIK3CA or PTEN mutations. For patients with ESR1 alterations, we had the recent approval for elacestrant [Orserdu] based on the [phase 3] EMERALD study [NCT03778931].

For patients who lack any of those genomic alterations, the current standard of care would potentially be to offer fulvestrant. We still have other options, like everolimus [Afinitor] with exemestane [Aromasin], as well as standard chemotherapy or later-line options, such as antibody-drug conjugates. In the second-line setting, fulvestrant and fulvestrant with alpelisib, capivasertib, or potentially elacestrant are currently the main options. There might be some debate as to when you might want to deploy elacestrant, [however].

We will soon see some data from the [phase 3] postMONARCH study [NCT05169567] looking again at the second-line population. Here, the question is: what is the utility of continued abemaciclib after progression in the first-line setting? This is an international randomized study looking at fulvestrant and placebo vs fulvestrant plus abemaciclib. That will be the first prospective phase 3 data providing some insight into CDK4/6 inhibition after prior CDK4/6 inhibition. Most of those patients will likely have [been previously exposed to] either palbociclib or ribociclib.

Instead of using fulvestrant, [ELAINE-3] is going to compare fulvestrant and abemaciclib with lasofoxifene and abemaciclib. If the postMONARCH study demonstrates some degree of clinical benefit, the ELAINE-3 study will extend our understanding of that by showing how much more clinical benefit we can glean by modifying the anti-estrogen to something that could have a better track record in heavily pretreated patients who have ESR1 and other known genomic alterations.

What are the potential clinical implications of the ELAINE-3 and postMONARCH trials for the management of hormone-receptor positive, HER2-negative breast cancer? How do these studies open future avenues for research?

If both studies are positive, it will create an increasingly complex spectrum of options in that second-line setting. You could imagine a scenario where, in addition to those targeted agents I just mentioned, we could be looking at abemaciclib with lasofoxifene for the ESR1-mutant patients. For the ESR1 wild-type patients, we might all also have the option of, for example, fulvestrant with abemaciclib. Not to mention, there is a whole host of other next-generation, oral selective estrogen receptor degraders, PROTACS, and other combinations with targeted agents and CDK4/6 inhibitors [being evaluated in the phase 3 setting].

We’ll have a lot of data from the phase 3 setting over the next couple of years looking at [these options]. It’s very complex, but it also provides many exciting opportunities to look at a patient’s genomic sequencing profile via either blood or solid tumor biopsy at the time of progression on standard first-line anti-estrogen and CDK inhibitor therapy. [This could] help us develop a treatment plan based on that genomic profile. We’re going to continue to build upon that paradigm and deliver better, individualized care for patients in the second- or third-line setting and beyond.

References

1. Sermonix Pharmaceuticals announces publication of ELAINE-1 and ELAINE-2 trial results in Annals of Oncology. News release. Sermonix Pharmaceuticals. December 11, 2023. Accessed January 18, 2024.
2. Goetz M, Wander S, Bachelot T, et al. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation. Presented at: 2023 San Antonio Breast Cancer Conference; December 5-9, 2023; San Antonio, TX. Abstract PO1-18-12.