Fine-Tuning Sequential Endocrine and Targeted Therapy in Advanced Hormone Receptor–Positive Breast Cancer
Presented by:
Kari Wisinski, MD, University of Wisconsin Carbone Cancer Center
Conference:
2025 University of Kansas Breast Cancer Year in Review
Introduction: A Therapeutic Landscape in Flux
In her presentation at the 2025 University of Kansas Breast Cancer Year in Review presented by Total Health, Dr Kari Wisinski discussed the increasingly nuanced pathways for managing hormone receptor–positive (HR+), Human epidermal growth factor receptor negative (HER2-) metastatic breast cancer (MBC). “This is one of the most rapidly evolving areas in oncology,” she remarked. “Our challenge is not a lack of treatment options—it’s sequencing and personalization.”
Her presentation focused on first-line decision-making, integration of novel agents like phosphatidyl inositol 3 kinase (PI3K) inhibitors and oral selective estrogen receptor degraders (SERDs), and the management of patients after progression on cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). Using data from landmark trials, real-world evidence, and emerging biomarker tools, Dr Wisinski outlined a framework for optimizing clinical care in this patient setting.
First-Line Therapy: CDK4/6 Inhibitors Remain Foundational—But Not Without Debate
Dr Wisinski reviewed clinical data on the CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—which, when combined with endocrine therapy (ET), remain a standard first-line treatment. While all three agents offer similar progression-free survival (PFS) benefits, overall survival (OS) data have favored ribociclib, particularly considering data from the MONALEESA studies. She also referenced the P-VERIFY real-world analysis, a study led by Dr Hope Rugo, which showed no significant OS difference among the three CDK4/6 inhibitors. She cautioned, however, that palbociclib dominated the dataset overall, which limited definitive conclusions. Dr Wisinski noted, “In clinical practice, ribociclib might be preferred due to the OS benefit, but all three remain reasonable—especially when individual toxicities and patient preference are factored in.”
SONIA Trial: Do All Patients Need First-Line CDK4/6 Inhibitors?
Dr Wisinski also noted findings from the SONIA trial, which added another nuance to this recommendation, specifically, asking whether deferring CDK4/6i use to second line (after progression on ET alone) would result in similar long-term outcomes. In SONIA, postmenopausal women with HR+/HER2– MBC received aromatase inhibitor (AI) monotherapy in the first line, followed by fulvestrant with or without CDK4/6i at progression. Overall, the results of the trial showed no significant improvement in PFS2 with upfront CDK4/6 inhibition. “These were endocrine-sensitive patients,” she emphasized, “so the findings may not apply to everyone—but they give us flexibility. Especially for patients worried about cost, side effects, or frequent monitoring, delayed CDK4/6i is a valid approach.”
New Tools: Can We Predict Who Truly Benefits from CDK4/6 Inhibition?
Dr Wisinski also highlighted some data from the 2024 San Antonio Breast Cancer Symposium (SABCS) wherein machine learning models were utilized to integrate clinical and genomic features to predict response to CDK4/6 inhibitors. Patients could be stratified into risk groups with vastly different PFS—from 5 months to nearly 30 months. “This is exactly where we need to go—toward personalized decision-making,” she noted. “Biomarkers that go beyond clinical intuition.”
Adding PI3K Inhibitors in First Line: The INAVO120 Trial
Dr Wisinski reviewed findings from the recent INAVO120 trial, which evaluated the addition of inavolisib (a selective PI3Kα inhibitor) to fulvestrant and palbociclib in patients with PIK3CA-mutant MBC who had progressed within 12 months of endocrine therapy. Results showed a doubling of PFS, at 15.0 versus 7.3 months, with an OS benefit also reported in a January 2025 press release. Adverse events in the trial were as expected, with diarrhea, hyperglycemia, and rash observed early during treatment, although these events were largely manageable. “This is a key option for select patients with evidence of early endocrine resistance and a PIK3CA mutation,” she said, while acknowledging limitations of the study: “Only 25% of patients in the placebo arm received a subsequent PI3K inhibitor. So we still need to ask—could we achieve the same benefit with sequential therapy?”
First-Line Chemotherapy vs. CDK4/6 Inhibitors: RIGHT Choice and PADMA Trials
Dr Wisinski noted the longstanding debate about using chemotherapy upfront, and findings from the RIGHT Choice and PADMA trials, which were designed to challenge the assumption that chemotherapy is superior for those with symptomatic or high-burden disease. In RIGHT Choice, Dr Wisinski noted that Ribociclib in combination with an AI outperformed doublet chemotherapy in terms of PFS, and the benefit was seen even among patients with visceral crisis. In addition, findings from PADMA showed that palbociclib with ET was superior to single-agent chemotherapy for patients with less aggressive disease. “These trials confirm that CDK4/6 inhibitors should remain first-line—even in patients with high burden or symptomatic disease” Dr Wisinski noted. “Chemotherapy should be reserved for truly endocrine-refractory cases or visceral crisis.”
Beyond First Line: What to Do After CDK4/6 Inhibitor Progression?
Dr Wisinski reviewed results from several trials exploring whether a continuation of CDK4/6 inhibition after progression provides benefit. In the PALMIRA and PACE trials, she noted that no benefit was seen for patients continuing palbociclib with a switch in their ET. In MAINTAIN, Dr Wisinski noted a modest PFS benefit when switching both ET and CDK4/6i, particularly for patients switching from palbociclib to ribociclib. Lastly, in PostMONARCH, Dr Wisinski noted that the combination of abemaciclib with fulvestrant improved PFS over placebo with fulvestrant (6-month PFS, 50% versus 37%), although the benefit was modest (median PFS 7.4 versus 6.7 months). “These studies suggest a second CDK4/6i can be reasonable in select patients,” Dr Wisinski noted, “especially when no targetable mutation is present. But we still need biomarkers to guide this decision.”
Oral SERDs: ESR1 Mutations and the Role of Elacestrant and Imlunestrant
Regarding patients with mutations in the estrogen receptor gene ESR1 Dr Wisinski noted the availability of oral selective estrogen receptor degraders (SERDs), particularly elacestrant, which has shown the greatest benefit for patients with ESR1-mutated tumors after progression on CDK4/6i in the EMERALD trial. She further noted findings for imlunestrant in the EMBER-3 trial which also improved PFS in ESR1-mutated tumors as compared to standard ET. Most notably, Dr Wisinski noted the combination of imlunestrant with abemaciclib, which showed superior PFS over imlunestrant alone, and the benefit was seen regardless of ESR1 mutation status. “These data support the use of oral SERDs for patients with ESR1 mutations,” she said. “And combination with CDK4/6 inhibition is looking increasingly compelling.”
PI3K/AKT/mTOR Pathway Inhibitors: A Refined Landscape
For patients in the third-line or later setting, Dr Wisinski reviewed the evolving use of specific pathway inhibitors. She noted that alpelisib, an inhibitor of PI3Kα is effective but can often be poorly tolerated. Capivasertib is an inhibitor of AKT, and seems to shows better tolerability and is currently approved for use in patients with PIK3CA, AKT1, or PTEN alterations based on CAPItello-291 trial. Dr Wisinski further noted that everolimus, an inhibitor of the mTOR pathway remains a reasonable option for selected patients without actionable alterations. “We need to be testing broadly—genomic and germline—to identify who benefits from which strategy,” she emphasized. “Especially now that these agents are better tolerated.”
Summary and Treatment Algorithm
Summarizing her presentation, Dr Wisinski outlined her current treatment algorithm for advanced HR+ breast cancer, which emphasizes and adaptable and patient-centered approach:
In the First Line, Dr Wisinski recommends ET + a CDK4/6i (preferably ribociclib or abemaciclib). A PI3Ki triplet with inovolisib can be considered for patients with early endocrine resistance and a PIK3CAmutation.
In the Second Line: Dr Wisinski recommends an oral SERD (elacestrant) if ESR1-mutated, or a switch in CDK4/6i if the patient is mutation-negative. If the PI3K pathway is altered, fulvestrant with capivasertib would be recommended.
In the Third Line and Beyond: Dr Wisinski recommends Capivasertib for PI3K pathway-altered tumors, everolimus for others, and chemotherapy or the antibody-drug conjugates (e.g., T-DXd or SG) as appropriate.
Fine-Tuning Sequential Endocrine and Targeted Therapy: Key Takeaways
CDK4/6 inhibitors remain the standard in first-line HR+/HER2– MBC, with ribociclib showing the strongest OS benefit.
Delaying CDK4/6 inhibition is a reasonable option for endocrine-sensitive patients, based on the SONIA trial.
Inavolisib + palbociclib + fulvestrant is a promising new option for PIK3CA-mutant, early progressing MBC.
Oral SERDs offer a targeted benefit in patients with ESR1-mutant disease, especially after failure on a CDK4/6i.
Capivasertib may replace alpelisib for patients with PI3K pathway–altered tumors, owing to its better tolerability.
Sequencing must be individualized, and future tools—particularly clinico-genomic biomarkers—may help to better optimize treatment decisions.
“It’s not just about the drugs anymore—it’s about using the right drug, at the right time, for the right tumor biology. That’s how we truly fine-tune therapy for our patients.”
You can see the full presentation by Dr Wisinski from the 2025 University of Kansas Breast Cancer Year in Review here.
Speaker Disclosure Information: Dr Wisinski reported no relevant disclosures for this presentation.