Shifting Treatment Paradigms in Hormone Receptor–Positive Breast Cancer 

Jasmin Hundal, MD Cleveland Clinic

Key Points

• Updated adjuvant trial data are reshaping CDK4/6 inhibitor selection, with ribociclib expanding into intermediate-risk early-stage disease and abemaciclib remaining preferred for node-positive patients based on overall survival (OS) benefit.

• Oral selective estrogen receptor degraders (SERDs) are poised to redefine endocrine backbones, with lidERA data positioning giredestrant as a promising adjuvant option pending longer follow-up and clarity on CDK4/6 inhibitor integration.

• PI3Kα-targeted therapy has entered a new era, as inavolisib became the first agent in its class to demonstrate an OS benefit in high-risk, PIK3CA-mutant, endocrine-resistant disease.

• Sequencing after CDK4/6 inhibitor exposure is increasingly guided by OS data, prior agent selection, and disease-free interval, with ribociclib emerging as a favored frontline option in metastatic disease.

• Comprehensive genomic profiling at progression is now essential, informing targeted therapy selection, rechallenge strategies, and use of emerging agents when actionable mutations are absent.

The landscape of hormone receptor (HR)–positive breast cancer continues to rapidly evolve, with recent data reshaping treatment algorithms from early-stage disease through metastatic settings. A recent expert panel discussion featuring Kevin Kalinsky, MD, MS, of Emory University School of Medicine, and Dr. Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center, highlighted key developments. 

Selecting Adjuvant CDK4/6 Inhibitors: Updates From NATALEE 

For early-stage disease, the choice between abemaciclib and ribociclib now requires nuanced consideration. The updated NATALEE trial data presented at the 2025 European Society for Medical Oncology (ESMO) Annual Congress demonstrated a “carrier effect” with ribociclib, showing a 4.5% improvement in invasive disease-free survival for intermediate-risk, node-negative patients, a population initially met with reluctance. This validates the broader inclusion criteria, including T2N0 high-risk disease.

Dr. Kalinsky emphasized that for node-positive patients, he still prefers abemaciclib, given its demonstrated 1.8% OS advantage at 7 years. The panelists noted critical practical differences: Ribociclib requires ovarian suppression in premenopausal patients and cannot be combined with tamoxifen, whereas abemaciclib permits both options from the monarchE trial. Clinicians should also remain vigilant about increased venous thromboembolism risk when combining abemaciclib with tamoxifen.

Advancing Endocrine Therapy: lidERA and Oral Selective Estrogen Receptor Degraders 

Giredestrant, a selective estrogen receptor degrader (SERD), has generated significant excitement—it represents the first major advancement in endocrine options in 25 years, potentially offering a more effective backbone than the current standard of care. In lidERA, 4,170 patients, 59% of whom were postmenopausal, were randomly assigned 1:1 to receive either giredestrant or physician’s choice of one of four endocrine therapies. All patients received surgery, and if indicated, adjuvant or neoadjuvant chemotherapy. 

After a median follow-up of 32.3 months, giredestrant-treated patients were 30% less likely to develop invasive disease progression than patients treated with standard-of-care endocrine therapy. Although still immature, preliminary analysis demonstrated a positive OS trend in favor of giredestrant. However, the experts emphasized the need for longer follow-up, especially in medium- and high-risk patients. 

CDK4/6 inhibitor integration remains a critical unanswered question. Given that 7-year data now demonstrate overall OS for CDK4/6 combinations, giredestrant’s performance when combined with these agents is essential. Randomized trials currently under way, including CAMBRIA-2 and substudy data evaluating abemaciclib plus giredestrant safety, will address this gap. The evERA trial (giredestrant plus everolimus vs exemestane plus everolimus) also will provide important sequencing data.

Defining the Role of PI3Kα-Targeted Therapy in Endocrine-Resistant Disease

The INAVO120 study established inavolisib (Itovebi) as a practice-changing option for a very specific population: PIK3CA-mutant patients with endocrine-resistant disease (progression on or within 12 months of adjuvant endocrine therapy). This trial enriched for the highest-risk patients by requiring measurable disease, resulting in PIK3CA mutations being predominantly detected in circulating tumor DNA, a marker of high tumor burden. The updated data showed PFS improvement to 17 months and, critically, the first OS benefit for PI3K pathway inhibition in breast cancer. Dr. Jhaveri emphasized the stark reality that 10% of patients in the control arm died within 6 months, underscoring the aggressive biology in this population.

Hyperglycemia management is paramount. Panelists recommended proactive strategies including prophylactic metformin, dietary modifications, endocrinology consultation, and dose modifications to maintain patients on therapy.

Optimizing Sequencing in Metastatic Disease After CDK4/6 Exposure

The optimal sequencing of therapies following CDK4/6 inhibitor exposure continues to evolve, driven largely by emerging OS data. Among available agents, ribociclib has become a preferred frontline CDK4/6 inhibitor for many clinicians due to the consistent OS benefit demonstrated across clinical trials. Abemaciclib is frequently used in the second-line setting following progression.

In patients with prior adjuvant CDK4/6 inhibitor exposure, treatment decisions are influenced by the specific agent used and the disease-free interval. If a patient previously received adjuvant abemaciclib and did not experience early recurrence, clinicians may consider reintroducing a CDK4/6—most commonly ribociclib—in the metastatic setting. Although rechallenge with an alternative CDK4/6 inhibitor is not yet standard, emerging trial data support this strategy in selected patients. Palbociclib, however, has largely fallen out of favor in high-risk populations, as it has not demonstrated a definitive OS benefit.

Managing Progression After Endocrine Therapy Plus CDK4/6 Inhibition

Upon progression on frontline endocrine therapy plus a CDK4/6 inhibitor, liquid next-generation sequencing is routinely obtained to identify actionable genomic alterations. In patients with PIK3CA, AKT, or PTEN pathway alterations, several targeted treatment options may be considered.

Fulvestrant plus capivasertib is often favored for patients with pathway alterations based on efficacy signals, although clinicians must carefully balance benefit against higher rates of rash and diarrhea compared with alternative regimens. Fulvestrant plus everolimus, supported by BOLERO-2 data, remains a viable option and demonstrates benefit regardless of PIK3CA mutation status.

Gedatolisib-based combinations represent an emerging option. Early data show promising activity in PIK3CA wild-type disease, with mutant subset results eagerly awaited. Practical limitations include intravenous administration (3 weeks on, 1 week off) and quarterly intramuscular injections, creating a substantial logistical and toxicity burden that may limit uptake in community practice.

Emerging Trials Poised to Refine Treatment Sequencing

Several ongoing and recently reported trials are expected to further refine sequencing strategies. For example, evERA is evaluating giredestrant plus everolimus versus exemestane plus everolimus. EMBER-3, which is assessing imlunestrant as monotherapy, in combination with standard endocrine therapy, or with abemaciclib, is of particular interest given observed benefit regardless of ESR1 mutation status.

Together, these evolving data underscore the importance of comprehensive genomic profiling at progression to guide personalized therapy selection. In the absence of actionable mutations, treatment decisions should incorporate:

• Pattern and tempo of disease progression
• Prior duration of benefit from CDK4/6 inhibition
• Patient tolerance and comorbidities

Options in this setting include CDK4/6 inhibitor rechallenge, antibody–drug conjugates, or chemotherapy, with sequencing tailored to individual disease biology and clinical context.