SABCS 2025: Redefining Endocrine-Based Care in HR+, HER2-Negative Breast Cancer Across Early and Metastatic Settings

This article reviews key clinical trial data that inform contemporary management of hormone receptor–positive (HR+), HER2-negative breast cancer across early and metastatic disease. The discussed studies span both adjuvant and advanced settings, including evaluations of oral selective estrogen receptor degraders (SERDs), CDK4/6 inhibitor–based strategies, endocrine therapy combinations, and antibody–drug conjugates (ADCs). Positive trials such as lidERA, MonarchE, MONALEESA, NATALEE, EMBER-3, ELEVATE, and PADMA demonstrate meaningful improvements in invasive disease–free survival (iDFS), progression-free survival (PFS), and overall survival (OS) with endocrine-based, chemotherapy-sparing approaches. At the same time, ASCENT-07 provides important negative data clarifying the limitations of earlier ADC use in hormone receptor-positive (HR+)/HER2-negative disease. Collectively, these results reinforce a biology-driven treatment paradigm, refine therapeutic sequencing, and support evidence-based decision-making to optimize long-term outcomes across the ER+, HER2– breast cancer continuum.

IidERA (NCT04961996)^{1, 2}

• Phase 3, global, randomized study comparing the investigational oral SERD giredestrant with standard of care endocrine therapy as adjuvant treatment for patients with medium- or high-risk early-stage ER+, HER2-negative breast cancer following surgery. The study enrolled over 4,100 participants and assessed iDFS as the primary endpoint, demonstrating a statistically significant improvement with giredestrant at interim analysis.

• The IidERA trial represents the first demonstration in over two decades that a novel endocrine agent can outperform existing standard adjuvant therapies, such as aromatase inhibitors and tamoxifen for ER+ early breast cancer, achieving a 30% reduction in the risk of invasive disease recurrence or death.

• If approved, giredestrant could become a new standard of care adjuvant endocrine therapy, offering enhanced iDFS and a favorable safety profile compared with current options, potentially improving long-term outcomes for a large portion of patients with ER+ early breast cancer.

ASCENT-07 (NCT05840211)^{3, 4}

• Phase 3, global, randomized study evaluating sacituzumab govitecan-hziy (Trodelvy) versus physician’s choice single-agent chemotherapy in patients with locally advanced unresectable or metastatic HR+/HER2-negative breast cancer who have progressed after endocrine therapy and are candidates for first-line cytotoxic chemotherapy. The primary endpoint was PFS assessed by blinded independent central review, with secondary endpoints including OS, objective response rate, quality of life, and safety. The study did not demonstrate a statistically significant improvement in PFS for sacituzumab govitecan compared with standard chemotherapy in this setting.

• ASCENT-07 sought to extend the therapeutic role of a Trop-2-directed ADC into HR+/HER2-negative disease earlier in the treatment course, addressing an unmet need for better options once endocrine therapy fails and before conventional chemotherapy. While sacituzumab govitecan has proven benefit in other metastatic breast cancer subtypes, particularly TNBC and later-line HR+/HER2-negative disease, ASCENT-07’s negative PFS outcome indicates that this approach does not meaningfully delay progression in endocrine therapy-refractory, chemotherapy-naive HR+/HER2-negative disease.

• ASCENT-07 results suggest that sacituzumab govitecan should not supplant standard first-line chemotherapy following endocrine therapy resistance in HR+/HER2-negative metastatic breast cancer, as no PFS benefit was shown. Treatment decisions in this population should continue to rely on established chemotherapy regimens, with sacituzumab govitecan reserved for its approved indications and disease settings with demonstrated efficacy (e.g., later-line HR+/HER2-negative or TNBC), while ongoing follow-up may further clarify any OS or subgroup signals.

EMBER-3 (NCT04975308)^{5, 6}

• Phase 3, randomized, open-label, active-controlled, multicenter trial in patients with ER+/HER2-negative, locally advanced or metastatic breast cancer (after prior endocrine therapy). Patients were randomized 1:1:1 to receive either the oral SERD Imlunestrant alone, investigator-choice standard endocrine therapy (fulvestrant or exemestane), or Imlunestrant combined with the CDK4/6 inhibitor Abemaciclib.

• In the subgroup of patients who had progressed on prior endocrine therapy (many after CDK4/6 inhibitors), Imlunestrant + Abemaciclib significantly prolonged PFS compared with Imlunestrant alone (median PFS = 9.4 months versus 5.5 months (imlune monotherapy)) and longer than standard-of-care endocrine therapy. Imlunestrant monotherapy showed modest PFS improvement over standard endocrine therapy, primarily in patients with ESR1-mutant tumors.

• These data support Imlunestrant (especially with Abemaciclib) as a viable, all-oral, second-line therapy with CDK4/6 inhibitors. The combination may offer a clinically meaningful PFS benefit and overcome some endocrine resistance (including ESR1 mutation-associated), potentially shifting the post-DCK4/6 inhibitor treatment paradigm away from injectable therapies.

The MONALEESA Clinical Trial Program^{7, 8}

• The program consists of large, Phase 3, randomized studies evaluating the CDK4/6 inhibitor ribociclib in combination with endocrine therapy versus endocrine therapy alone in patients with HR+/HER2-negative advanced or metastatic breast cancer, including both postmenopausal and pre-perimenopausal populations. Across all three trials, the primary endpoint was PFS with key secondary endpoints, including OS and safety.

• MONALEESA is the only CDK4/6 inhibitor program to consistently demonstrate statistically significant and clinically meaningful OS benefit across multiple disease settings, including first-line, second-line, and premenopausal patients. These data firmly established ribociclib as a therapy that not only delays progression but also prolongs life, setting a high evidentiary bar within the CDK4/6 inhibitor class.

• Study results support ribociclib plus endocrine therapy as a preferred standard of care option for HR+/HER2-negative metastatic breast cancer across a broad range of patients. The demonstrated OS benefit, coupled with a predictable and manageable safety profile, provides strong justification for prioritizing ribociclib when selecting CDK4/6 inhibitor-based regimens in appropriate patients.

NATALEE (NCT03701334)^{9, 10}

• Phase 3, global, randomized study evaluating ribociclib plus standard adjuvant endocrine therapy versus endocrine therapy alone in patients with stage II-III HR+/HER2-negative early breast cancer, including a broader risk population than prior CDK4/6 adjuvant trials. Ribociclib was administered at a lower dose (400 mg) for 3 years, with iDFS as the primary endpoint.

• NATALEE demonstrated a statistically significant improvement in iDFS, establishing that CDK4/6 inhibition can provide meaningful benefit in the adjuvant setting, even among patients with intermediate-risk disease. The trial expanded the evidence base beyond very high-risk populations, differentiating ribociclib from earlier studies that failed to show consistent benefit in early breast cancer.

• This study supports ribociclib plus endocrine therapy as a potential adjuvant treatment option for a wider range of patients with HR+/HER2-negative early breast cancer, not limited to those with the highest recurrence risk. The reduced ribociclib dose and extended duration aim to balance efficacy with tolerability, making patient selection, adherence, and monitoring key considerations in real-world implementation.

MonarchE (NCT03155997)^{11, 12}

• Phase 3, randomized, open-label trial comparing 2 years of adjuvant Abemaciclib + standard endocrine therapy versus endocrine therapy alone in patients with HR+/HER2-negative, node-positive, high-risk early breast cancer.

• In the intent-to-treat population (5,637 patients), Abemaciclib + endocrine therapy significantly improved iDFS compared to endocrine therapy alone (HR ~ 0.75). Updated long-term follow-up shows sustained benefit: at 4 years, absolute IDFS difference ~6.4% (85.5% versus 79.4%).

• The data support adjuvant Abemaciclib + endocrine therapy as a new standard for high-risk HR+/HER2-negative, node-positive early breast cancer — reducing recurrence risk (including distant relapse) and improving long-term outcomes. The 2025 OS analysis demonstrates a ~15.8% reduction in risk of death versus endocrine therapy alone, marking the first OS benefit of a CDK4/6 inhibitor in this setting.

ELEVATE (NCT05563220)^{13, 14}

• Phase 1b/2, open-label, umbrella study testing combinations of the oral SERD Elacestrant with various targeted agents (including PI3K/mTOR inhibitors, CDK4/6 inhibitors, and other pathway inhibitors) in patients with ER+/HER2-negative metastatic breast cancer. The Phase 1b portion determines the recommended Phase 2 dose of elacestrant when combined with partners such as Everolimus, Ribociclib, Abemaciclib, Palbociclib, Alpelisib, and others; the Phase 2 portion will assess efficacy.

• The trial builds on prior data showing single-agent elacestrant improved PFS versus standard endocrine therapy in ER+/HER2-negative, ESR1-mutant metastatic breast cancer after CDK4/6 inhibitor exposure; however, resistance mechanisms remain frequent. ELEVATE aims to overcome these resistance pathways by pairing elacestrant with agents targeting cell‑cycle (CDK4/6), PI3K/AKT/mTOR, and other signaling networks. Early phase data indicate that combinations such as elacestrant + everolimus or elacestrant + ribociclib are tolerable and produce promising PFS (e.g. ~8.3 months with elacestrant + everolimus) in a heavily pretreated metastatic setting.

• If confirmed in phase 2 and beyond, ELEVATE may validate an all-oral, chemotherapy-free backbone (elacestrant) plus targeted agents for ER+/HER2-negative metastatic breast cancer, potentially offering a convenient, tolerable alternative for patients after prior endocrine therapy ± CDK4/6 inhibitors. This could shift second-line (or later) management, delaying cytotoxic chemotherapy or ADC use, especially in patients with endocrine-resistant disease.

PADMA trial (NCT03355157)^{15, 16}

• Phase 3, prospective, randomized, open-label, multi-center trial comparing first-line therapy with Palbociclib + endocrine therapy versus choice mono-chemotherapy (with or without maintenance endocrine therapy) in patients with metastatic, HR+/HER2-negative breast cancer.

• In this real-world setting, the palbociclib + ET arm achieved a significantly longer median time to treatment failure (TTF), 17.2 versus 6.1 months (HR ~ 0.46; p < 0.001), and a longer PFS of 18.7 versus 7.8 months (HR ~ 0.45; p < 0.001) compared with chemotherapy alone. This represents the first randomized data directly comparing endocrine therapy + CDK4/6 inhibitor versus chemotherapy as first-line treatment in high-risk HR+/HER2– metastatic breast cancer.

• The findings support endocrine therapy + palbociclib as a preferred first-line regimen over chemotherapy in patients with HR+/HER2– metastatic breast cancer who otherwise might receive mono-chemotherapy, thus aligning prospective data with guideline recommendations. The improved TTF and PFS suggest longer disease control, potentially sparing patients from chemotherapy toxicity, delaying cytotoxic exposure, and improving quality of life and treatment tolerability.

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