Phase 2 Data Support Development of Lasofoxifene in ESR1-mutant, ER+/HER2– Breast Cancer

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Jane Lowe Meisel, MD, discusses previously reported data from the ELAINE-1 and ELAINE-2 trials, their significance within the ESR1-mutant, ER-positive, HER2-negative breast cancer treatment paradigm, and the purpose of the ongoing ELAINE-3 trial.

Jane Lowe Meisel, MD

Jane Lowe Meisel, MD

Ongoing development of the selective estrogen receptor (ER) modulator lasofoxifene (Fablyn) could lead to improved quality of life (QOL) and long-term survival in patients with ESR1-mutant, ER-positive, HER2-negative breast cancer, potentially providing an effective alternative to fulvestrant (Faslodex), according to Jane Lowe Meisel, MD.

Prior phase 2 data on lasofoxifene as monotherapy and in combination with abemaciclib (Verzenio) illustrated the agent’s robust antitumor activity against metastatic ER-positive, HER2-negative breast cancers with ESR1 mutations.

Findings from the phase 2 ELAINE-1 trial (NCT03781063) presented at the 2022 ESMO Congress showed that lasofoxifene displayed antitumor activity despite missing the primary end point of progression-free survival (PFS).1 Recently reported data from a small-sample-sized secondary analysis of this trial indicated that the regimen is associated with decreased vaginal and vulvar symptoms compared with fulvestrant, elucidating lasofoxifene’s potential ability to improve treatment tolerability.2

Findings from the phase 2 ELAINE-2 trial (NCT04432454) demonstrated improved median PFS of 13 months, and an objective response rate of 50% with the use of lasofoxifene plus abemaciclib in this patient population. These updated findings were presented at the 2022 ASCO Annual Meeting.3

Both trials support the initiation of the phase 3 ELAINE-3 study, which will evaluate lasofoxifene or fulvestrant plus abemaciclib in pre- and postmenopausal patients in this disease setting.4

“When [patients] received a diagnosis of metastatic breast cancer 5 to 10 years ago, they were [mostly] thinking about how long they could survive. [However], having good lives and enjoying those lives is also important [for these] patients,” said Meisel, who is an associate professor in the Department of Hematology and Medical Oncology and an associate professor in the Department of Gynecology and Obstetrics at Emory University School of Medicine in Atlanta, Georgia.

In an interview with OncLive®, Meisel discussed previously reported data from the ELAINE-1 and ELAINE-2 trials, as well as their significance within the paradigm. Meisel also expanded on the purpose of the ongoing ELAINE-3 trial, and how the continued investigation of lasofoxifene in this disease setting reinforces the need to prioritize patients’ QOL during treatment.

OncLive: Please describe the design and key objectives of the ELAINE-1 trial. What results have been reported thus far from this study, and how are they relevant to the paradigm?

Meisel: The study [included] 102 patients. These were all patients with metastatic ER-positive breast cancer, who had progressed on an aromatase inhibitor [AI] and CDK4/6 inhibitor. All patients in the trial also had to have an ESR1 mutation in their cancer. PFS was the primary end point.

Final results showed that [median] PFS was 6 months with lasofoxifene and 4 months with fulvestrant. [This finding] was not statistically significant, but [was] clinically significant enough to warrant further study [of] this drug. The clinical benefit rate [CBR] was also higher for the lasofoxifene group, [at 36.5%] vs [21.6% with] fulvestrant. It was quite interesting [to see] how many patients made it to 12 months on [lasofoxifene] without progressing. The 12-month PFS rate was 30.7% for the lasofoxifene group vs 14.1% [with] fulvestrant. If you think about that in terms of real-life [benefit], patients [have about a] one-third chance of not progressing 1 year [after] starting an oral medication. That’s a nice [prognosis], and those results were encouraging. [Although these findings are] not yet practice changing, [they] certainly make the drug worthy of further study.

What should physicians know about the toxicity profile of lasofoxifene, based on safety analysis in ELAINE-1?

[Lasofoxifene] is an interesting drug. It was originally developed to prevent osteoporosis, primarily [by] strengthening bone. Then it was found to both prevent bone loss and prevent breast cancer. It’s a selective ER modulator, and with that comes a slightly increased risk of blood clots. The other main [toxicities] that we saw in some of these studies are hot flashes, a little bit of nausea, and some fatigue. From what we’ve seen so far, it seems to be a very safe agent. Of course, being able to take it orally and once a day is nice for patients.

What other symptoms can arise in patients being treated with an ER inhibitor in ESR1-mutated metastatic breast cancer?

Some of the challenges associated with anti-estrogen treatment for ER-positive breast cancer include vulvovaginal symptoms. These are hard for people to talk about and it’s an uncomfortable topic, so patients don’t always bring it up. When you deprive someone of estrogen in this natural way, you can end up with vaginal dryness. That can lead to pain [and] frequent urinary tract infections. It can [also cause] pain with intercourse, which can affect personal relationships and be psychologically distressing. As providers are learning more about this, we are training ourselves to ask more about [these symptoms]. We do find that when we ask, [patients will admit they’re] suffering from this. It’s important to deal with [in terms of] patients’ QOL.

Given the data recently reported from the secondary analysis of vaginal/vulvar symptoms in ELAINE-1, how might lasofoxifene help decrease the burden of these symptoms?

This sub-study was looking at vulvovaginal atrophy in patients who were enrolled in ELAINE-1. [Patients] completed vulvovaginal assessment scales looking at sexual health and pain. Investigators found that lasofoxifene was associated with improved vulvovaginal symptoms compared with fulvestrant. If this [agent] provides clinical benefits for patients, [including] better vaginal and sexual health, they get better QOL and potentially stay on treatment longer.[According to] what we saw in ELAINE-1, [lasofoxifene’s] efficacy is a bit better than or [comparable to fulvestrant] and the adverse effects [AEs] are better. Combined, [these data provide] a compelling alternative to what we’re currently giving.

Shifting over to the ELAINE-2 trial, what was the rationale for conducting this investigation of lasofoxifene plus abemaciclib in this population?

[Based on] some of the earlier studies looking at lasofoxifene, [investigators] thought that because of the way that it works, it may help [address] some of these vulvovaginal symptoms. That would be a real boon for patients. If you had a medicine that not only did not worsen those [AEs] but might improve them, QOL could be better.

This small, phase 2 study looked at the combination of lasofoxifene and abemaciclib, which is one of the CDK4/6 inhibitors. The rationale behind that trial design is that we know prolonged treatment with AIs can lead to acquired ESR1 mutations in the cancer. [These mutations] activate the ER constitutively. This means that it’s turned on all the time, and that cells can divide and respond to the ER whether estrogen is [bound]. This leads to resistance to AIs and worsened prognosis in these patients.

For patients with ESR1 mutations, we’ve seen that lasofoxifene can potentially be beneficial. In other studies, we’ve also seen that patients can derive benefit from abemaciclib after progressing on prior ribociclib [Kisqali] or palbociclib [Ibrance]. There were also some preclinical data supporting the combination of lasofoxifene with the CDK4/6 inhibitor. The researchers in ELAINE-2 combined abemaciclib with lasofoxifene to see what kind of outcomes they would get.

What efficacy and safety data were reported from ELAINE-2?

There were 29 patients in this study, and they were a pretty heavily pretreated population in terms of [prior] endocrine therapy. Most [patients] had at least 2 prior hormonal treatments, and [79.3%] had seen fulvestrant already. Interestingly, the efficacy was quite good in this study. The median PFS, [or] the median amount of time that patients were on this treatment before they progressed, was [13] months, and the CBR for the combination was [69%]. Again, [this was] clinically significant. [The regimen] was well tolerated and the efficacy data were meaningful, although it was a small population.

We [already] know a lot about the toxicities of abemaciclib, which typically include nausea, diarrhea, and [decreased] white blood cell counts. We did see that but there were no new safety signals [with the combination].

These findings have inspired the upcoming ELAINE-3 trial of lasofoxifene plus abemaciclib versus fulvestrant plus abemaciclib. Why should this combination continue to be evaluated in ER-positive, HER2-negative breast cancer, and what does ELAINE-3 seek to contribute to the treatment landscape?

With each new drug that gets approved, we have new standards of care that evolve. This trial is going to compare lasofoxifene and abemaciclib with fulvestrant and abemaciclib instead of fulvestrant alone. It’s looking at abemaciclib in patients with an ESR1 mutation, and then seeing how they do with fulvestrant vs lasofoxifene as the endocrine partner. Investigators plan to enroll 400 patients, so it will be a larger study. These patients [must] have previously progressed on an AI plus either palbociclib or ribociclib. This is a specific patient population, but [it is one] that we see a lot in clinical practice.

The trial will look at PFS as the primary measure. Secondary outcomes are looking at other clinically important [end points] like how long [patients] respond for, differences in QOL, and AEs. Importantly, [the trial is also evaluating] how long it takes patients to get to their first chemotherapy after they’ve had these combinations. [It would be] significant if you were to find that one combination [that could] prolong the time to chemotherapy.

What else might be learned from the continued investigation of lasofoxifene in this population? What should your colleagues ultimately take away from this research?

As we further investigate the role [of] lasofoxifene in the armamentarium against metastatic breast cancer, we’re learning about the importance of QOL. We have so many good treatments for patients with metastatic disease now, and patients are living longer [because of them]. In some cases, it really can become [akin to a] high-maintenance chronic illness, but it’s not just about survival. [A lot] of attention is being paid to the drug’s AEs in development, and how [they] affect QOL and sexual health. [These trials serve as] an important reminder that we need to consider not just length of life, but QOL as we treat these patients.


  1. Goetz MP, Plourde P, Stover DG, et al. 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. Ann Oncol. 2022;33(suppl 7):S1387-S1388. doi:10.1016/j.annonc.2022.08.015
  2. Sermonix’s lasofoxifene improves vaginal/vulvar symptoms relative to fulvestrant in ELAINE 1 study of postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer and an ESR1 mutation. News release. Sermonix Pharmaceuticals, Inc. March 6, 2023. Accessed April 4, 2023.
  3. Damodaran S, Plourde PV, Moore HCF, et al. Open-label, phase 2, multicenter study of lasofoxifene (las) combined with abemaciclib (abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer and an ESR1 mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022
  4. Sermonix Pharmaceuticals announces initiation of phase 3 ELAINE-3 study of lasofoxifene plus abemaciclib in pre- and post-menopausal patients with locally advanced or metastatic ER+/HER2- breast cancer with an ESR1 mutation as detected by guardant health’s guardant360 CDx liquid biopsy. News Release. Sermonix Pharmaceuticals. March 9, 2023. Accessed April 4, 2023.
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