PURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

The treatment of metastatic breast cancer (mBC) has evolved significantly in the past several years with the approval of new targeted agents. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate with a topoisomerase I inhibitor payload, is a new addition to the class of therapies that target the human epidermal growth factor 2 (HER2) receptor. T-DXd was approved in the US in December 2019 for patients with HER2-positive metastatic or unresectable breast cancer who have received 2 or more prior anti-HER2–based regimens in the metastatic setting. In the DESTINY-Breast01 phase II trial (NCT03248492), T-DXd demonstrated high rates of durable responses in heavily pretreated patients with HER2-positive mBC, with a confirmed objective response rate of 62%, median duration of response of 18.2 months, and median progression-free survival of 19.4 months. In addition to efficacy, successful implementation of any new anticancer therapy includes learning how to prevent, monitor, and manage treatment-related adverse events. As T-DXd becomes more widely used, information can be gained from real-world clinical practices, institutional approaches, and the collaboration of multidisciplinary oncology teams who treat patients with T-DXd. This article reviews practical insights and management of nausea and vomiting, neutropenia, interstitial lung disease, risk of cardiotoxicity, and other adverse events associated with T-DXd administration from the perspective of health care providers who have experience utilizing T-DXd.

Background: Endocrine therapy(ET) plus CDK4/6 inhibitor (i) is the mainstay for the management of estrogenreceptor-positive (ER+)/HER2- mBC. However, most patients (pts) with ER+ mBCeventually experience disease progression, including development of ESR1mutations (mESR1). Elacestrant, an oral SERD, demonstrated preclinical activity,and clinical activity in a phase 1 trial in ER+ mBC, including responses in ptswith prior fulvestrant, CDK4/6i, and mESR1tumors (Bardia JCO 2021).. Methods: EMERALD(NCT03778931), a multicenter, international, randomized, open-label, controlledphase 3 trial, enrolled postmenopausal pts with ER+/HER2- mBC who had received 1-2prior lines of ET and ≤1 line of chemotherapy in the mBC setting and had prior progressionon a ET plus CDK4/6i. Pts were randomized 1:1 to elacestrant (400 mg orallydaily) or standard of care (SOC; investigator’s choice of fulvestrant or anaromatase inhibitor). Stratification factors included mESR1 status (by central lab), priorfulvestrant exposure, and presence of visceral disease. The study had 2 primary endpoints of progression-free survival (PFS), by blindedindependent review committee, in pts withtumors harboring mESR1 and in all pts (mESR1 or mESR1 notdetected). Secondary endpoints included: overall survival (OS), safety, tolerability,and quality of life. An alpha-value of 0.0475 was used to determine statisticalsignificance (2-sided using the truncated Hochberg procedure).. Results: EMERALD enrolled 477 pts(228 with mESR1) between Feb 2019 - Oct 2020, with 239 pts randomized toreceive elacestrant vs 238 pts to SOC. Demographics and disease characteristicswere well-balanced across treatment arms [median age: 63 yrs vs 63.5 yrs; 2prior lines: 46% vs 40.8%; prior CDK4/6i: 100% in both arms]. The study met bothprimary endpoints. There was a 30% reduction in the risk of progression ordeath in the elacestrant arm in all pts (HR=0.697 [95% CI: 0.552, 0.88]; P=0.0018),and a 45% (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005) reduction in therisk of progression or death in pts with mESR1.For both endpoints, results in key prespecified subgroups, including visceral metastases,number of prior lines of therapy, pretreatment with fulvestrant, and geographicalregion, were consistent with the overall outcome. The PFS rate at 12 months was 22.32% (95% CI: 15.24%, 29.40%)with elacestrant vs 9.42% (95% CI: 4.02%, 14.81%) with SOC in all pts, and26.76% (95% CI: 16.17%, 37.36%) vs 8.19% (95% CI: 1.26%, 15.12%) in the mESR1 subgroup. The prespecified interim OS analysis plannedat the time of the final PFS analysis (allocated2-sided alpha level of 0.0001) demonstrated a trend in favor of elacestrant inall pts (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in pts with mESR1(HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325). The final OS analysisis expected next year. Common (>10%) treatment-related adverse events (AEs) withelacestrant vs SOC included: nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%), mostlygrade 1/2. Treatment-emergent AEs leading to discontinuation of elacestrant orSOC were infrequent in both arms (6.3% and 4.4%). Grade ≥3 treatment-relatedAEs in the elacestrant arm vs SOC were 7.2% vs 3.1%, mainly driven by nausea(2.1% vs 0.9%). There were no treatment-related deaths in either group.. Conclusions:Elacestrant is the first oral SERD to demonstrate a statistically significantand clinically meaningful improvement of PFS vs SOC in a randomized phase 3study in pts with ER+/HER2- mBC in the 2nd/3rd-linesetting, including those whose tumors harbor mESR1. Elacestrant was well tolerated and hasthe potential to become the new standard of care for pts with ER+/HER2- mBC. Citation Format: Aditya Bardia, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frédéric Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Peter Vuylsteke, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Virginia Kaklamani, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, José García-Sáenz, Emilio Bria, Marina Cazzaniga, Janice Lu, Philippe Aftimos, Javier Cortes, Shubin Liu, Dirk Laurent, Maureen G. Conlan, Francois-Clement Bidard. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-02.

Next generation sequencing (NGS) coupled with sophisticated bioinformatics tools yields an unprecedented amount of information regarding tumor genetics, with the potential to reveal insights into tumor behavior. NGS and other multiplex genomic assays are rapidly spilling from the laboratory into the clinic through numerous commercial and academic entities. This raises the important question as to whether we are ready to use these data in clinical decision-making. While genetic lesions are clearly targeted by a new generation of biological cancer therapies, and certain regulatory approvals are actually coupled to single gene assays, we still do not know if the vast information on other genomic alterations is worth the added cost, or even worse, the inappropriate and unproven assignment of patients to treatment with an unapproved drug carrying potentially serious side effects. On the other hand, the trend toward a precision medicine pathway is clearly accelerating, and clinical trials validating pathway-driven personalized cancer therapeutics will be necessary in both the community and academic settings. Lower cost and wider availability of NGS now raises a debate over the merit of routine tumor genome-wide analysis.

1050 Background: Novel degraders and antagonists of ER are under evaluation in aBC, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant, the only approved SERD. ER is also overexpressed in ̃80% of EEC and endocrine therapy (ET) is utilized for these patients (pts). LY3484356, a novel, orally bioavailable SERD with pure antagonistic properties results in sustained inhibition of ER-dependent gene transcription and cell growth. Preclinically, LY3484356 shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants. Here we present the initial clinical data from EMBER, an ongoing first-in-human phase 1a/b trial of this novel agent. Methods: Phase 1a evaluated LY3484356 dose escalation (i3+3 design) in women with ER+, HER2- aBC (≤3 prior therapies for aBC following protocol amendment; prior ET sensitivity) and ER+ EEC (prior platinum therapy). Premenopausal women received a concomitant GnRH agonist. Key endpoints included determination of the recommended phase 2 dose, safety and tolerability, PK, and objective response rate and clinical benefit rate per RECIST v1.1. Results: As of the data cut (November 9, 2020), 28 pts (n = 24 aBC, n = 4 EEC) were enrolled at doses ranging from 200-1200 mg QD. Median age was 59 years (range, 35-80). Median number of prior therapies for aBC was 2 (range, 1-8; 6 pts enrolled prior to protocol amendment had received ≥4 prior therapies), including prior fulvestrant (46%), a CDK4/6 inhibitor (83%), and chemotherapy (33%). No dose-limiting toxicities were observed. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (32%), fatigue (25%), and diarrhea (18%). The only grade 3 treatment-related AE was diarrhea (n = 1). TEAEs of bradycardia and QTc prolongation were not observed despite intensive central ECG monitoring. Dose-proportional increases in LY3484356 exposures were observed across all evaluated doses and t1/2 was 25-30 hours. At the starting dose level (200 mg QD), unbound LY3484356 exposures exceeded those achieved with fulvestrant. 16 of 28 pts were efficacy evaluable, with the remaining 12 pts ongoing prior to first scan. Among 16 evaluable pts, 11 (8 aBC, 3 EEC) had stable disease (10 pts ongoing), and 5 had progressive disease. RECIST responses were observed after the data cut and will be detailed at the meeting. Plasma ctDNA analysis indicated decreases in mutant allele frequencies, including mutant ESR1 in 9/12 (75%) evaluable pts across all dose levels. Conclusions: LY3484356 QD dosing shows favorable safety and PK properties, along with preliminary efficacy in pts with heavily pretreated ER+ aBC and EEC. Updated data will be presented at the meeting. Clinical trial information: NCT04188548 .