Evolving Strategies in the Management of HR+, HER2– Metastatic Breast Cancer

Hormone receptor (HR)–positive, HER2-negative breast cancer represents the most prevalent subtype of the disease, accounting for approximately 70% of all breast cancers.¹ Advances in systemic therapies over the past 2 decades have markedly improved outcomes, enabling longterm disease control in a substantial proportion of patients. As a result, metastatic HR-positive, HER2-negative breast cancer is often regarded as a highly treatable disease, where therapeutic goals extend beyond prolonging survival to include the preservation of quality of life. The historical management paradigm has relied on sequential endocrine therapy (ET) until resistance, followed by cytotoxic chemotherapy, but this framework has been redefined by the integration of targeted agents with ET.² Therapeutic decisions in the metastatic setting are influenced not only by clinical features, such as timing of recurrence and prior therapies, but also increasingly by consideration of tumor biology, including endocrine sensitivity or resistance, and evaluation of tumor mutational profiles.³

For patients presenting with de novo metastatic disease or with recurrence occurring 12 months or more after the completion of adjuvant ET, the standard first-line treatment globally is ET plus a CDK4/6 inhibitor, in combination with ovarian function suppression for premenopausal women. In clinical practice, ribociclib (Kisqali) and abemaciclib (Verzenio) are the most commonly prescribed partners with an aromatase inhibitor (AI), with selection largely guided by toxicity profiles, comorbidities, and patient preferences.^4,5 In exceptional circumstances, such as limited access to a CDK4/6 inhibitor or significant toxicity concerns, ET alone may be initiated in the first line, with consideration of fulvestrant plus a CDK4/6 inhibitor introduced at progression.6 Upon progression on a CDK4/6 inhibitor/ AI backbone, treatment selection should be individualized according to disease aggressiveness, duration of benefit from prior ET, organ function, and molecular testing results. Patients who remain candidates for further ET may receive fulvestrant (Faslodex) or an alternate endocrine partner in combination with targeted therapies directed against specific alterations, such as alpelisib (Piqray) for PIK3CA mutations, capivasertib (Truqap) for PI3K/ AKT/PTEN alterations, elacestrant (Orserdu) or imlunestrant (Inluriyo) for ESR1 mutations, or a PARP inhibitor for germline BRCA1/2 or PALB2 mutations.^7-12 For patients without targetable alterations, options include everolimus (Afinitor)–based combinations or, in selected cases with prolonged benefit from prior therapy, continuation of CDK4/6 inhibition beyond progression with abemaciclib or ribociclib.10,13,14 In contrast, patients no longer suitable for ET or targeted therapy approaches should be transitioned to antibody-drug conjugates or sequential single-agent chemotherapy, with fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu) prioritized for those with HER2-low or -ultralow disease, followed by sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan-dlnk (Dato-DXd, Datroway), or conventional cytotoxic agents, including capecitabine (Xeloda) and taxanes.^15-18 Across these therapies, careful attention to patient selection and proactive supportive care are essential, as many targeted agents carry distinct toxicity profiles—such as rash, diarrhea, hyperglycemia, hepatotoxicity, or hematologic adverse effects—that may require prophylactic or symptom-directed interventions.

Patients who relapse on adjuvant ET or within 12 months of its completion constitute a distinct subgroup with a more resistant disease profile. This recurrence pattern reflects primary or secondary endocrine resistance and has underscored the importance of resistance mechanisms in guiding therapy. Somatic PIK3CA mutations are detected in approximately 30% to 40% of HR-positive, HER2-negative metastatic breast cancers, and recent data with the triplet of fulvestrant, palbociclib (Ibrance), and inavolisib (Itovebi) demonstrated improved progression-free survival (PFS) and overall survival compared with fulvestrant plus palbociclib, establishing the need for molecular testing at initial time of metastatic diagnosis in this setting.^19,20 For patients with PIK3CA wild-type tumors, fulvestrant combined with a CDK4/6 inhibitor remains the standard first-line therapy. Increasingly, recurrences may occur after adjuvant treatment with a CDK4/6 inhibitor, and in these cases, first-line therapy must be individualized: Although some patients may still benefit from rechallenge, others should be considered CDK4/6-refractory and transitioned directly to subsequent lines.²¹ This decision is influenced by the interval between completion of adjuvant CDK4/6 inhibitors and relapse, the clinical pattern of recurrence, and patient characteristics, all of which help define whether retreatment is appropriate. Beyond first-line therapy, the overall treatment principles mirror those applied after progression on CDK4/6 inhibitors in endocrine-sensitive disease.

The next wave of innovation in HR-positive, HER2-negative metastatic breast cancer is being driven by novel endocrine agents and adaptive treatment strategies. Oral selective estrogen receptor degraders (SERDs) represent a key advance, particularly in the setting of endocrine resistance, with the potential to improve efficacy, tolerability, and patient convenience compared with the existing intramuscular SERD, fulvestrant. As monotherapy, oral SERDs have consistently demonstrated superior activity in ESR1-mutated HR-positive/HER2-negative metastatic breast cancer when compared with standard endocrine options, leading to the respective FDA approvals for elacestrant, based on the phase 3 EMERALD study (NCT03778931), and imlunestrant, based on the phase 3 EMBER-3 study (NCT04975308).^7,12 However, oral SERDs may show best performance when used in combinations, as supported by emerging data. In EMBER-3, the combination of imlunestrant with abemaciclib yielded clinically meaningful improvements in PFS compared with imlunestrant alone, irrespective of ESR1 status.^12,22 Likewise, the phase 3 evERA trial (NCT05306340) was recently announced to have met its co–primary end points, with the oral SERD giredestrant plus everolimus demonstrating an improvement in PFS compared with a provider- choice endocrine therapy with everolimus in the post-CDK4/6 setting, further supporting the role of all-oral SERD-based combinations.^23,24

The phase 3 SERENA-6 trial (NCT04964934) further underscored the potential of molecularly informed treatment adaptation.²⁵ In this trial, in patients receiving AI and CDK4/6 inhibitors as part of first-line therapy, switching from an AI to the oral SERD camizestrant at the time of emergent ^ESR1 mutation—“molecular progression” detected by circulating tumor DNA (ctDNA) but prior to radiographic progression— led to a significant prolongation in PFS compared with continuing on the original regimen.25 Results from this trial represent a paradigm shift toward considering ctDNA-guided interventions, raising the possibility that molecular monitoring could become routine in tailoring f irst-line therapy.

Beyond SERDs, the phase 3 VERITAC-2 trial (NCT05654623) of the investigational proteolysis-targeting chimera ER degrader vepdegestrant achieved a significant improvement in PFS compared with fulvestrant in patients with ESR1-mutated tumors, providing clinical proof of concept for this novel class.26 Additionally, results from the phase 3 VIKTORIA-1 trial (NCT05501886) were recently announced, demonstrating that gedatolisib, a dual PI3K/mTOR inhibitor, combined with fulvestrant with or without palbociclib, achieved superior PFS compared with fulvestrant alone in patients with PIK3CA wild-type previously treated with a CDK4/6 inhibitor plus an AI.^27,28 In parallel, development of more selective PI3K/AKT/PTEN pathway inhibitors, including next-generation mutant-specific PI3K and AKT inhibitors, is ongoing.29 These agents aim to improve tolerability while maintaining potency, potentially broadening eligibility to patients with comorbidities such as prediabetes or obesity.

Together, these advances highlight a future defined by precision-driven and adaptive treatment, where real-time molecular profiling informs dynamic therapeutic choices. Key challenges ahead will include integrating ctDNA into standard care, optimizing sequencing of novel endocrine and targeted agents, and ensuring that increasingly complex regimens remain feasible and well tolerated.