Updates on SERD Trials for Metastatic Breast Cancer

Sara Hurvitz, MD

Associate Professor, David Geffen School of Medicine

Medical Director, Jonsson Comprehensive Cancer Center Clinical Research Unit

Codirector of the Santa Monica-UCLA Outpatient Oncology Practices

Director of the Breast Cancer Clinical Trials Program

University of California, Los Angeles

Santa Monica, CA

Targeted Oncology^TM: What makes ESR1 mutations significant to patients with metastatic breast cancer treatment?

HURVITZ: The common or defined ESR1 mutations [are in] different regions and the hotspot, the area with the largest number of mutations, activating mutations in ESR1 are found in the ligand binding domain and AFT2.¹ The most common are [E380Q, Y538 C/D/H/N/S, and D538G/N], so you’ll see a lot of patients with D538G and Y537.

We know from datasets like the analysis of the SoFEA clinical trial [NCT00253422], which was a randomized study of fulvestrant [Faslodex] vs exemestane, a much older study, that patients with ESR1 mutations tend to do worse with AI [aromatase inhibitor] therapy.² Looking at progression-free survival [PFS], for the patients who have a tumor that is wild type for ESR1, exemestane [Aromasin] and fulvestrant look equivalent, but fulvestrant does much better than the exemestane-treated patients in the presence of an ESR1 mutation.

The overall survival [Kaplan-Meier] curve shows the same thing. This was the first evidence that you might want to select fulvestrant or something that works differently than an AI in the presence of ESR1 mutations.

How has the development of selective estrogen receptor degraders (SERDs) accelerated in recent years?

Let’s recall the history of SERDs. Fulvestrant was first approved in 2002 but it wasn’t until 2006 or 2007 that they realized we were giving it at too low a dose.³ And once we did the dose that was appropriate, 500 mg with a loading dose in the first month, we began to see that fulvestrant was as good or maybe better than AIs. Then came the combination strategies with palbociclib [Ibrance] later on and then alpelisib [Piqray] with an FDA approval in 2019,⁴ and so it has been almost 20 years later that we see oral SERDs in development, and indeed 21 years later that we see the FDA approval of the first oral SERD.⁵ However, we’ve also seen a disappointing pathway where we’ve seen a number of oral SERDs drop out of development due to negative results.

[There are studies of] combinations with CDK4/6 inhibitors in the frontline setting. We haven’t seen results from these yet, and AMEERA-5 [NCT04478266] was halted.⁶ In patients who have already received a CDK4/6 inhibitor, you have a number of studies. EMERALD [NCT03778931] was a positive study,⁷ but we had acelERA [NCT04576455] and AMEERA-3 [NCT04059484] that were negative trials.^8,9 SERENA-2 [NCT04214288], presented at San Antonio was a positive study,¹⁰ but keep in mind that not all SERDs are demonstrating positive data. We also have a lot of basket studies looking at combinations of oral SERDs with other pathway inhibitors and we have data from the early-stage setting as well.

What led to the approval of elacestrant (Orserdu) in this patient population?

The EMERALD study is…the one that led to the approval of elacestrant [that looked at] 466 patients.⁷ Patients had to have had 1 or 2 prior lines of endocrine therapy and up to one line of chemotherapy, and they also had to have a prior CDK4/6 inhibitor, but the [criteria] didn’t require an ESR1 mutation, however, all patients had their mutation status checked. The primary end point was PFS in all patients and then PFS in patients with an ESR1 mutation. The [comparator] arm was anastrozole [Arimidex], exemestane, letrozole [Femara], or fulvestrant based on investigator choice.

I would just [note] that two-thirds of patients had visceral metastases. This is not a patient population with light bone-only disease. It is also important to see that about 20% of patients or so had previously received chemotherapy in the metastatic setting, [which is] a minority. Roughly 40% of patients had had 2 lines of endocrine therapy for metastatic disease. Also, [approximately] a quarter of patients received previous fulvestrant and are still going on this study of an oral SERD.

A minority of patients, less than 5% overall, received a PI3 kinase pathway inhibitor, and at this point, my use of elacestrant might be after a PI3 kinase pathway inhibitor like everolimus [Afinitor] or alpelisib. However, EMERALD didn’t study, to a large extent, the activity of elacestrant in those patients who’d already had that treatment, so the data may be stronger for elacestrant earlier.

[The study reported] PFS in all patients and in those harboring a mutant ESR1. There was a statistically significant improvement in PFS in favor of elacestrant compared with standard of care. The absolute improvement was on the order of a few months.

_REFERENCES

_{1. Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125(21):3714-3728. doi:10.1002/cncr.32345}

_{2. Turner NC, Swift C, Kilburn L, et al. ESR1 mutations and overall survival on fulvestrant versus exemestane in advanced hormone receptor-positive breast cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials. Clin Cancer Res. 2020;26(19):5172-5177. doi:10.1158/1078-0432.CCR-20-0224}

_{3. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. doi:10.1200/JCO.2010.28.8415}

_{4. FDA approves alpelisib for metastatic breast cancer. News release. FDA. May 24, 2019. Updated May 28, 2019. Accessed March 16, 2023. https://bit.ly/30Lzsak}

_{5. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. January 27, 2023. Accessed March 16, 2023. https://bit.ly/42cX1c1}

_{6. Sanofi provides update on amcenestrant clinical development program. Press release. Sanofi; August 17, 2022. Accessed March 16, 2023. https://bit.ly/3ArwdbP}

_{7. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338}

_{8. Jimenez MM, Lim E, Mac Gregor MC, et al. Giredestrant (GDC-9545) vs physician choice of endocrine monotherapy (PCET) in patients (pts) with ER+, HER2– locally advanced/metastatic breast cancer (LA/mBC): primary analysis of the phase II, randomised, open-label acelERA BC study. Ann Oncol. 2022;33(suppl 7):S633-S634. doi:10.1016/j.annonc.2022.07.250}

_{9. Tolaney SM, Chan A, Petrakova K, et al. 212MO - AMEERA-3, a phase II study of amcenestrant (AMC) versus endocrine treatment of physician’s choice (TPC) in patients (pts) with endocrine-resistant ER+/HER2− advanced breast cancer (aBC). Ann Oncol. 2022;33(suppl_7):S88-S121. doi:10.1016/annonc/annonc1040}

_{10. Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial. 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas; abstract GS3-02.}