SERDs Represent the Next Generation of ER-Targeting Therapy in Breast Cancer

Selective estrogen receptor degraders (SERDs) are becoming increasingly important in the treatment of ER-positive metastatic breast cancer (MBC), Erika P. Hamilton, MD, said during a presentation at the 20th Annual International Congress on the Future of Breast Cancer® East meeting, hosted by the Physicians’ Education Resource® (PER®), LLC.

“You get to be the first to know all about these before they hit the clinic, but they will be here soon and probably in multiple different lines of therapy,” noted Hamilton, director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon.

Hamilton highlighted promising new therapeutic strategies for MBC. At present, there are 10 oral SERDs in development, along with a handful of selective estrogen receptor covalent antagonists (SERCAs), selective estrogen receptor modulators (SERMs), and agents in other categories.

Patients with ER-positive disease have been treated with elective modulation of ER for more than 30 years, primarily with SERMs and aromatase inhibitors. Unfortunately, up to half patients develop drug resistance within 3 to 5 years.²

Fulvestrant (Faslodex) is the only FDA-approved SERD indicated for the treatment of endocrine-resistant breast cancers. However, the drug’s poor pharmacokinetic properties have inspired the development of a new generation of oral SERDs to overcome drug resistance.

Early data with oral SERDs has demonstrated encouraging clinical activity, although objective response rates (ORRs) have not been impressive. ORR across all compounds in phase 1 testing range from 5% to 15%. However, Hamilton said ORR is the wrong metric to measure the efficacy of SERDs.

“What is meaningful for us is progression-free survival [PFS] or clinical benefit rate [CBR] at a conservative definition of 6 months,” Hamilton said. “We know that patients coming off aromatase inhibitors and CDK4/6 inhibitors do not tend to do as well as they used to on our currently available endocrine therapies. This is the big unmet clinical need — to get compounds in that work after CDK4/6 inhibitors.”

In the phase 1 AMEERA-1 study (NCT03284957), investigators evaluated a standard dose of palbociclib (Ibrance) along with amcenestrant (SAR439859) at 200 mg (n = 9) and 400 mg (n = 6) daily (QD), and in a dose expansion cohort (n = 30) at 200 mg QD. Eligible patients must have been heavily pretreated, and postmenopausal, with ER-positive, HER2-negative MBC. Additionally, patients had to have received at least 6 months of prior endocrine therapy in the advanced setting, as well as chemotherapy in the advanced setting.³

Lead author Sarat Chandarlapaty, MD, PhD, a medical oncologist with Memorial Sloan Kettering Cancer Center, presented the preliminary results of the study at the 2021 ASCO Annual Meeting. In the pooled population at the 200 mg dose (n = 35), the ORR was 34.3%, with no complete responses (CR) and 12 partial responses (PR). Moreover, the CBR was 74.3% (90% CI, 59.4%-85.9%).

Hamilton noted that a significant percentage of patients derived benefit at 6 months, a result she called “quite impressive.” However, she pointed out that only 5% of patients had received CDK4/6 inhibitors, which may account for the high levels of activity.

Based on these findings, investigators have initiated a phase 3 combination study AMEERA-5 (NCT04478266) evaluating amcenestrant/palbociclib with letrozole in the first-line setting.

Investigators led by Marina Maglakelidze, MD, with ARENSIA Exploratory Medicine LLC in Tiblisi, Georgia, also presented data showing clinical benefit for patients with ER-positive, HER2-negative breast cancer assigned to a SERD plus palbociclib at ASCO. In part 3 of a phase 1, dose-escalation/expiation trial, patients with advanced disease (n = 40) were the assigned to 800 mg rinodestrant (G1T48) plus 125 mg palbociclib QD for 21 days of a 28-day cycle. The median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%).⁴

Among 40 patients enrolled, 2 (5%) had a confirmed PR, and 26 (68%) had stable disease, and 28 (70%) remained on study treatment.

The CBR jumped from 30% to 60% when investigators added palbociclib to rintodestrant, Hamilton noted. The CBR among the full set of patients was 60%, and the median PFS was 7.4 months (95% CI, 3.7­–not reached), though the data are not mature.⁵

References

1. Hamilton, E. Promising New Therapeutic Strategies for Metastatic Breast Cancer. Presented at: 20th Annual International Congress on the Future of Breast Cancer® East; July 16-17, 2021; virtual.
2. Lu Y, Liu W. Selective estrogen receptor degraders (SERDs): a promising strategy for estrogen receptor positive endocrine-resistant breast cancer. J Med Chem. 2020;63(24):15094-15114. doi:10.1021/acs.jmedchem.0c00913
3. Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). J Clin Oncol. 2021,39 (suppl 15; abstr 1058). doi:10.1200/JCO.2021.39.15_suppl.1058
4. Maglakelidze M, Bulat I, Ryspayeva D, et al. Rintodestrant (G1T48), an oral selective estrogen receptor degrader, in combination with palbociclib for ER+/HER2– advanced breast cancer: Phase 1 results. J Clin Oncol. 2021,39 (suppl 15; abstr 1063). doi:10.1200/JCO.2021.39.15_suppl.1063
5. G1 Therapeutics. G1 Therapeutics presents phase 1 data at ASCO describing favorable safety profile and evidence of antitumor activity of rintodestrant combined with palbociclib in patients with ER+/HER2- advanced breast cancer. News release. June 4, 2021. Accessed July 19, 2021. https://bit.ly/3is0ltr