Oncology

HR+ HER2- Breast Cancer

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Selective Estrogen Receptor Degraders and Other Novel Agents in Breast Cancer: Where Do We Stand?

conference reporter by Sara M. Tolaney, MD, MPH

Overview

Endocrine therapy is an integral component of treatment for hormone receptor–positive/human epidermal growth factor receptor 2–negative (HER2-) breast cancer. Researchers at the 2023 ASCO Annual Meeting presented data from several studies evaluating selective estrogen receptor degraders (SERDs) and other novel agents targeting the estrogen receptor (ER) in this setting.

Following these presentations, featured expert Sara M. Tolaney, MD, MPH, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Tolaney’s clinical perspectives on these findings are presented here. 

Sara M. Tolaney, MD, MPH

Chief, Division of Breast Oncology
Associate Director, Susan F. Smith Center for Women’s Cancers
Senior Physician
Dana-Farber Cancer Institute
Associate Professor, Department of Medicine
Harvard Medical School
Boston, MA

“Fulvestrant is a SERD with limitations, such as the need for intramuscular injection and poor bioavailability.”

Sara M. Tolaney, MD, MPH

There are many ER-targeting agents that are coming down the pipeline, including novel SERDs, proteolysis targeting chimera (PROTAC) ER degraders, complete ER antagonists (CERANs), and selective estrogen receptor modulators. Fulvestrant is a SERD with limitations, such as the need for intramuscular injection and poor bioavailability. We currently have 1 novel oral SERD that is approved by the US Food and Drug Administration (ie, elacestrant) and others that are in development, including camizestrant, giredestrant, amcenestrant, imlunestrant, rintodestrant, and borestrant.

Elacestrant is approved for postmenopausal women and adult men with ER+/HER2-, ESR1-mutated, advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. Approval was based on the results of the phase 3 EMERALD trial, which demonstrated that elacestrant was associated with significantly improved progression-free survival (PFS) compared with standard-of-care therapy with endocrine monotherapy. The median PFS was only 3.8 months in patients with ESR1-mutated disease; however, a post hoc analysis of the EMERALD trial reported that patients with ESR1 mutations who had a prolonged exposure to a first-line CDK4/6 inhibitor (≥12 months) had a PFS benefit of up to 8.6 months.

The other novel oral SERDs are now in registration trials, where they are being compared head to head with endocrine monotherapy in the post–CDK4/6 inhibitor setting. Since fulvestrant has limited efficacy as monotherapy in the post–CDK4/6 inhibitor setting, standard of care is usually to combine fulvestrant with a targeted drug, such as everolimus or alpelisib, so these trials do not reflect the current treatment paradigms, making them difficult to interpret.

But there are also ongoing trials with camizestrant and giredestrant in the first-line space combining therapy with CDK4/6 inhibition to see if they are better than an aromatase inhibitor with CDK4/6 inhibition. And now, the SERDs giredestrant, amcenestrant, camizestrant, and imlunestrant are actually being studied in the adjuvant setting as well, in trials examining if they are more effective at preventing disease recurrence than an aromatase inhibitor, for example, in this setting. They moved quite quickly to the early-disease space, but they are early on in investigation, and we will have to see how things play out.

Other novel agents that target the ER in a different way include the PROTAC ER degrader ARV-471. There are data with ARV-471 as monotherapy that look very robust in very heavily pretreated ER+ disease. Another advantage of ARV-471 is that it has a favorable toxicity profile, with most side effects being grade 1 or 2. At ASCO 2023, Campone et al presented data from the phase 3 VERITAC-2 trial, which is comparing ARV-471 head to head with fulvestrant (abstract TPS1122). And there are other studies underway, such as the study by Layman et al describing the first substudies of TACTIVE-U, which is evaluating ARV-471 plus abemaciclib and ribociclib (abstract TPS1121). ARV-471 is also being evaluated in combination with palbociclib in the phase 2 cohort expansion of the VERITAC trial.

Finally, there are very interesting CERANs, such as OP-1250, that are under development and were discussed at ASCO 2023 (abstract TPS1127). Overall, there are a lot of novel oral agents targeting the ER that will, hopefully, improve on our current endocrine treatments.

References

Bardia A, Bidard FC, Neven P, et al. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting [abstract GS3-01]. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

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

Borges VE, Chan A, Lin NU, Tonda ME, Shilkrut M, Alemany CA. A phase 1b/2 dose escalation and expansion study of OP-1250 in combination with ribociclib or alpelisib in patients with advanced and/or metastatic estrogen receptor-positive (ER+)/HER2-negative (HER2-) breast cancer [abstract TPS1127]. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

Campone M, Ma CX, De Laurentiis M, et al. VERITAC-2: a global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer [abstract TPS1122]. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

ClinicalTrials.gov. A phase 1/2 trial of ARV-471 alone and in combination with palbociclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC). Updated June 5, 2023. Accessed June 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04072952

ClinicalTrials.gov. A study of camizestrant in ER+/HER2- early breast cancer after at least 2 years of standard adjuvant endocrine therapy (CAMBRIA-1). Updated June 15, 2023. Accessed June 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05774951

ClinicalTrials.gov. A study of imlunestrant versus standard endocrine therapy in participants with early breast cancer (EMBER-4). Updated May 30, 2023. Accessed June 27, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05514054

Downton T, Zhou F, Segara D, Jeselsohn R, Lim E. Oral selective estrogen receptor degraders (SERDs) in breast cancer: advances, challenges, and current status. Drug Des Devel Ther. 2022;16:2933-2948. doi:10.2147/DDDT.S380925

Hamilton E, Vahdat L, Han HS, et al. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract PD13-08]. Abstract presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX.

Layman RM, Jerzak KJ, Hilton JF, et al. TACTIVE-U: phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer [abstract TPS1121]. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

Turner NC, Jhaveri KL, Bardia A, et al. persevERA Breast Cancer (BC): phase III study evaluating the efficacy and safety of giredestrant (GDC-9545) + palbociclib versus letrozole + palbociclib in patients (pts) with estrogen-receptor-positive, HER2-negative locally advanced or metastatic BC (ER+/HER2– LA/mBC) [abstract TPS1103]. Abstract presented at: 2021 American Society of Clinical Oncology Annual Meeting; June 4-8, 2021.

Turner N, Huang-Bartlett C, Kalinsky K, et al. Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment. Future Oncol. 2023;19(8):559-573. doi:10.2217/fon-2022-1196

Wang Y, Tang S-C. The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options. Cancer Metastasis Rev. 2022;41(4):975-990. doi:10.1007/s10555-022-10066-y

 

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Sara M. Tolaney, MD, MPH

Chief, Division of Breast Oncology
Associate Director, Susan F. Smith Center for Women’s Cancers
Senior Physician
Dana-Farber Cancer Institute
Associate Professor, Department of Medicine
Harvard Medical School
Boston, MA

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