2026 Advances and Ongoing Challenges in HR-positive, HER2-Negative Metastatic Breast Cancer

Breast cancer is the most frequently diagnosed malignancy among women in the United States, affecting approximately 1 in 8 women.¹ The hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative subtype predominates in both early-stage and metastatic breast cancer (MBC).² In 2025, an estimated 319,750 new cases were diagnosed (316,950 women and 2,800 men), with approximately 42,680 breast cancer-related deaths.³ Despite substantial theraputic advances in MBC that have reduced overall mortality, female incidence rates have gradually increased since the mid‐2000s (~1% per year over the last decade) and patient prognosis remains poor, with a 5-year overall survival (OS) rate of ~32%.^{3, 4} In a recent review, Dr. Raghavendra and colleagues summarize current understandings in HR-positive/HER2-negative MBC biology, highlight mechanisms of endocrine-based therapy resistance, and outline the modern treatment landscape.³ This article synthesizes three key advances in HR-positive MBC management highlighted in the review: (1) integration of Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitors, (2) genomically-driven targeted therapies, and (3) expansion of Antibody-Drug Conjugates (ADCs) and other agents.³ Together, these developments provide new evidence that is expected to shape MBC treatment in 2026.

(1) Integration of CDK4/6 inhibitors: While endocrine therapy alone has historically been effective in treating MBC, resistance is common and remains a significant clinical challenge.³ CDK4/6 inhibitors were developed based on mechanistic insights into cell-cycle dysregulation, a hallmark of cancer pathogenesis.³ Combining CDK4/6 inhibition with endocrine therapy (typically aromatase inhibitors or fulvestrant) was initially hypothesized to cease proliferation in HR-positive MBC.³ In agreement, this combination has significantly improved progression-free survival (PFS) compared with endocrine therapy alone; some combinations (ribociclib + endocrine therapy) have demonstrated additional OS benefits in the Phase 3 MONALEESA Trials (2, 3, and 7).³ CDK4/6 inhibitors constitute a new standard of care for first-line therapy in HR-positive/HER2-negative MBC and have fundamentally shifted survival expectations and disease control durations.³ While it is worth noting that survival benefits are difficult to compare between different agents due to variations in population and treatment history among enrolled participants, data from the RIGHT Choice and ABIGAIL trials have demonstrated that this combined therapeutic approach led to positive impacts in patients with aggressive MBC disease burden and visceral crisis.³ Interestingly, data from the SONIA trial found no significant OS or disease-control advantage for first-line CDK4/6 inhibitor use compared with delayed administration, aside from reduced toxicity and cost.³ These findings highlight the need for individualized treatment decisions based on disease burden and patient priorities in the absence of predictive biomarkers.³ Overall, consistent gains in PFS and improvements in patient well-being demonstrate the transformative impact of CKD4/6 inhibitors on clinical outcomes for patients with HR-positive MBC.³

(2) Genomically-driven targeted therapies: While standard endocrine therapies remain foundational in first-line MBC treatment, acquired resistance is nearly universal and necessitates a genomically informed approach to optimize treatment and patient outcomes.³ Advances in sequencing technologies, primarily next-generation sequencing (NGS), facilitated the identification of biomarkers in the form of genomic alterations that contribute to endocrine resistance.³ These alterations are generally classified as gain-of-function or loss-of-function and emphasize the feasibility of highly-tailored and individualized therapeutic approaches.³ While tumor tissue remains the gold standard for establishing a baseline genomic landscape in MBC patients, NGS has enabled a less invasive liquid biopsy of circulating tumor DNA (ctDNA) that is especially useful for longitudinal monitoring and real-time tumor profiling in individualized approaches.³ Once these genomic alterations are identified, NGS allows for appropriate therapy matching and subsequent deployment of targeted inhibitors against PI3K and AKT, or Selective Endocrine Receptor Degraders (SERDs) for ESR1-mutant disease.³ Results from Phase 3 clinical trials (SOLAR-1, INAVO120, & EMERALD) have shown improvements in PFS and, in some cases, OS for genomically-driven targeted agents in appropriately selected populations.³ By integrating genomic profiling, clinicians can adapt therapy in response to acquired resistance signals that are detected through ctDNA and over the course of the disease.³

(3) Expansion of ADCs and other agents: Decades of monoclonal antibody engineering have led to the development of ADCs and Poly(ADP-Ribose) Polymerase inhibitors (PARPs), which selectively deliver cytotoxic payloads to tumor cells based on surface antigen expression.³ PARP inhibitors provide well-established clinical benefit in BRCA-deficient cancers and are now integrated into the management of HER2-negative, BRCA–mutated MBC.³ In the OlympiAD and EMBRACA trials, PARP inhibition significantly improved PFS, although no OS benefit was reported.³ Similarly, ADC-based regimens have demonstrated meaningful improvements in PFS, objective response rates (ORR), and disease control in the TROPiCS-02, TROPION-Breast01, and DESTINY-Breast06 trials, particularly in patients with disease refractory to endocrine therapy and CDK4/6 inhibitors.³ Although ADCs are most commonly deployed in the second-line or later settings, emerging evidence suggests that select high-risk patients may benefit from earlier ADC administration.³ This approach may be particularly beneficial for patients with NSG-identified genomic alterations indicative of increased symptom burden, endocrine resistance, or a lack of response to traditional first-line approaches.³ Collectively, the expansion of ADCs and PARPs has expanded the therapeutic landscape for advanced MBC beyond hormonal modulation, offering effective treatment options for tumors resistant to endocrine and targeted inhibitor-based strategies.³

Substantial progress has been made in the management of HR-positive, HER2-negative MBC. However, despite measurable advances from the implementation of the discussed therapeutic strategies, clinical gaps remain in overcoming resistance, optimizing treatment sequencing, developing predictive biomarkers, and integrating evidence into real-world practice.³ Addressing these challenges will require a shift from static treatment algorithms toward adaptive, biology-driven strategies that incorporate longitudinal molecular profiling, rational sequencing, and individualized risk assessment. As the therapeutic landscape for HR-positive, HER2-negative MBC continues to expand, future improvements will depend less on the availability of novel agents and more on the precision with which existing therapies are deployed across the disease continuum.

Sources:

1. Siegel, Rebecca L., et al. “Cancer Statistics, 2025.” CA: A Cancer Journal for Clinicians, vol. 75, no. 1, 16 Jan. 2025, acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21871, https://doi.org/10.3322/caac.21871. Accessed 30 Jan. 2026.
2. Shockney, Lillie. “Breast Cancer Facts & Statistics.” National Breast Cancer Foundation, 15 June 2023, www.nationalbreastcancer.org/breast-cancer-facts/. Accessed 30 Jan. 2026.
3. Singareeka Raghavendra, Akshara, et al. “Personalizing Therapies over the Course of Hormone Receptor‐Positive/HER2‐Negative Metastatic Breast Cancer.” CA: A Cancer Journal for Clinicians, vol. 76, no. 1, Jan. 2026, https://doi.org/10.3322/caac.70055.
4. American Cancer Society. Breast Cancer Facts & Figures 2024-2025. Atlanta: American Cancer Society; 2024. Accessed 30 Jan. 2026.