Oral SERDs and PI3K Inhibitors Move the Needle Beyond CDK4/6 Inhibitors in Metastatic Breast Cancer

Recent data have helped significantly shape the metastatic breast cancer treatment paradigm, particularly with more trials investigating treatments beyond CDK4/6 inhibitors, including oral selective estrogen receptor degraders (SERDs), including elacestrant (Orserdu), and PI3K inhibitors, according to Katherine C. Ansley, MD.

Of note, the FDA approved elacestrant in January 2023 for the treatment of estrogen receptor(ER)–positive, HER2-negative, ESR1-mutant advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. The approval was based on data from the phase 3 EMERALD trial (NCT03778931).1

Furthermore, in October 2024, the FDA approved inavolisib (Itovebi) plus palbociclib (Ibrance) and fulvestrant (Faslodex) for the treatment of patients with endocrine-resistant, PIK3CA-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test after recurrence on or after completing adjuvant endocrine therapy.2 The regulatory decision was supported by data from the phase 3 INOVA120 trial (NCT04191499).

“It’s an exciting time to be in breast cancer. We have [gained] so many more treatment options in the last few years to try to overcome the endocrine-resistant pathways. [However,] we need more,” Ansley said during an interview with OncLive®. “Unfortunately, ER-positive breast cancer is still considered incurable. We’re on the lookout for more agents, although I’m thrilled that we have so many [treatments] to offer now, and sometimes we can even sequence these agents too, and turn it more into a chronic disease and overcome these pathways of resistance.”

In the interview, Ansley highlighted efficacy data from an exploratory post-hoc analysis of EMERALD; the role of oral selective estrogen receptor degraders (SERDs), PI3K inhibitors, and AKT inhibitors in the metastatic breast cancer treatment paradigm; and how she approaches treatment selection, especially in patients with bone metastases.

Ansley is a breast medical oncologist at the Atrium Health Wake Forest Baptist Hematology and Oncology – Cancer Center and an associate professor of cancer medicine at the Wake Forest University School of Medicine in Winston-Salem, North Carolina.

OncLive: What were the key efficacy data from the exploratory post-hoc analysis of EMERALD?

Ansley: The updates that we saw in the exploratory post talk subgroup analysis that was published in Clinical Cancer Research in 2024 by Aditya Bardia, MD, MPH, FASCO. This [analysis] evaluated the progression-free survival [PFS] of patients who had received endocrine therapy.3 In terms of the group [with PIK3CA- and ESR1-mutant tumors], the [median] PFS [with elacestrant] was 5.5 months vs 1.9 months with standard of care [SOC]. In the PIK3CA wild-type group, the [median] PFS with elacestrant was 9.03 months [95% CI, 5.49-16.89] vs 1.87 months [95% CI, 1.87-3.71] with SOC. One of the other subgroups was [patients with] TP53-mutated disease, which tends to have a worse prognosis, overall. We still saw improvement in both the patients with disease harboring a TP53 mutation and those with wild-type [disease].

We also looked at those who had the existence of HER2-low expression because that’s another target that we now have other medications for, and we still see a response in [patients with] HER2-low [expression] vs those who are HER2-zero. The [median] PFS in patients with HER2-low expression was 9.0 months with elacestrant vs SOC being 1.9 months.

One of the other important aspects was whether patients [had bone-only] metastasis, or if they had liver or lung metastases. There was some concern initially if elacestrant would work in patients with more advanced visceral metastasis. In fact, we saw a significant response in [patients with] liver and lung metastases, with elacestrant, [demonstrating a]median PFS of 7.3 months vs 1.9 months with SOC [HR, 0.35; 95% CI, 0.21–0.59]. Patients with bone-only metastases did even better [with a median PFS of] 9.1 months in the elacestrant group, which are encouraging data. In general, one of the best things about elacestrant is how well it is tolerated. We didn’t see as many [adverse] effects [AEs] because it is a more endocrine therapy–based. One thing we’re always looking for as oncologist is to have drugs that work better with fewer AEs, and we are seeing that with these treatments.

How do oral SERDs fit into the metastatic breast cancer treatment paradigm?

They offer an important option in terms of overcoming endocrine resistance. We know that with first-line treatment with the aromatase inhibitors letrozole [Femara] and exemestane [Aromasin], and anastrozole [Armidex], the cancer figures out a way around it, and to be able to find that ESR1-mutation where now we have an active drug with elacestrant is quite exciting for us, and there are many more coming. We’re thrilled to have [a therapy] that is [FDA-]approved and effective at prolonging PFS.

How do you approach treatment selection, especially in patients with bone metastases?

I teach our fellows here that it depends on [patients’] duration of response [DOR] to their first line of therapy, whether they have bone-only or liver metastases. However, most of us believe that if patients have a longer DOR after their initial therapy, they’re more likely to have a sustained, durable response with these second-line oral SERDs.

Even though we have data from this trial, I still try them because it’s always nice to have an oral regimen. However, I’m expecting it to work better in my patients who have bone-only [metastases] and a longer DOR to their first-line therapy.

How do PI3K and AKT inhibitors fit into the treatment paradigm?

[We’ve seen] updates from the phase 2 BYLieve study [NCT03056766] with alpelisib [Piqray] plus fulvestrant in [patients with] PIK3CA mutation. We previously had data from the [phase 3] SOLAR-1 study [NCT02437318] that showed improvement of PFS [with alpelisib], but that was largely in a subset of patients who had not [received] a CDK4/6 inhibitor as first-line therapy. This BYLieve update was important, as it included patients who had received prior treatment with CDK4/6 inhibitors, and it [evaluated] alpelisib. This update that was published and presented at the 2020 ASCO Annual Meeting by Hope Rugo, MD, [specifically assessed] cohort A with alpelisib plus fulvestrant. It [started enrollment in] 2017, and the data cutoff was in 2022. We did see improvement in responses with a significant change from baseline and the measurable lesions. We assumed that this was going to be the case, but it was nice to see that update, and it makes us feel better about using it [after] CDK4/6 inhibitors.

[Regarding] updates from the [phase 3] CAPItello-291 study [NCT04305496], with capivasertib [Truqap] plus fulvestrant in patients with PIK3CA-mutated disease. This is another exciting agent that targets not only the PIK3CA mutation, but also AKT1 and PTEN. CAPItello-291 evaluated capivasertib plus fulvestrant vs placebo and fulvestrant in patients who had received at least 1 prior line of therapy in the first-line metastatic setting. We saw an improvement in PFS with the capivasertib plus fulvestrant in not just the patients with PIK3CA-mutated disease, but also in the AKT1-mutated population. We also saw trends in overall survival, which was pretty exciting. These drugs, when we consider the PIK3CA mutations, one of the things we’re worried about the most is some of the AEs. They do tend to have significantly more AEs than, for example, the oral SERDs. We are concerned about diarrhea, rash, and hyperglycemia. Rates of those with capivasertib are higher, which we’re aware of and monitor for.

[There’s also the] update with the [phase 2/3] INOVA120 trial [NCT04191499]. We had this trial open at Wake Forest and were able to enroll patients on it. This was an interesting study for patients with high-risk disease. It was a first-line study. Prior to this, we’d only been using PIK3CA inhibitors [in the] second line; however, this study was looking at patients who had progressed during or within 12 months of stopping their adjuvant endocrine therapy, whose cancer came back quickly. Even in that patient population, we did see an improvement with the triplet, which was inavolisib with palbociclib and fulvestrant.

References

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed July 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
2. FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. FDA. October 10, 2024. Accessed July 31, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive
3. Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30(19):4299-4309. doi:10.1158/1078-0432.CCR-24-1073