Advancing Treatment After CDK4/6 Inhibitor Progression in HR+/HER2– Breast Cancer

Breast cancer treatments have improved significantly over the past few decades, leading to better clinical outcomes for patients. The efficacy of contemporary cancer treatments can be attributed to novel targeted and immunotherapeutic agents capable of selectively targeting cancer cells, such as CDK4/6 inhibitor—a hallmark treatment for patients with hormone receptor-positive (HR+)/HER2-negative (HER2–) metastatic breast cancer (mBC).

Despite the demonstrated benefits of these agents, progression and poor clinical outcomes still occur for some patients, underscoring the need for more refined treatment strategies—because optimal outcomes depend not only on what therapies are available, but how they are applied in clinical practice.

At the 2025 San Antonio Breast Cancer Symposium, experts discussed treatment strategies for HR+/HER2– mBC following progression on CDK4/6 inhibitors. They highlight the growing role of next-generation endocrine therapies (ET), emerging resistance-targeting agents, and innovative clinical approaches.

Understanding HR+/HER2– Breast Cancer and CDK4/6 Inhibitors

HR+/HER2– metastatic breast cancer (mBC) is the most common breast cancer subtype, representing nearly 70% of all cases.¹ Patients with HER2 alterations often face a higher risk of recurrence and more aggressive disease biology, which can lead to resistance or progression despite standard therapies. As understanding of these molecular drivers has deepened, treatment strategies have evolved to better address both endocrine resistance and HER2-related signaling pathways.

Among the most notable developments are CDK4/6 inhibitors, which have become foundational in the management of HR+/HER2– mBC. The FDA-approved agents ribociclib (Kisqali; Novartis), abemaciclib (Verzenio; Eli Lilly), and palbociclib (Ibrance; Pfizer) have each demonstrated substantial improvements in efficacy and tolerability compared with traditional cytotoxic chemotherapy, reshaping the treatment landscape.

Targeting CDK4 and CDK6—key regulators of cell cycle progression—has proven particularly effective because HER2 signaling enhances CDK4/6 activity. This interconnection makes CDK4/6 inhibition an appealing approach for patients who develop resistance to HER2-directed therapies such as trastuzumab (Herceptin; Genentech Inc).^2,3

However, many patients still progress following these therapies, despite their established efficacy in clinical trial and real-world settings. This progression reflects the underlying genomic complexity of HR+/HER2– mBC, in which diverse resistance mechanisms emerge over time.

Predicting Response and Identifying Actionable Mutations

Next-generation sequencing (NGS) is a critical tool for predicting patient responses to CDK4/6 inhibitor therapy and making subsequent treatment decisions. When patients with HR+/HER2– mBC become resistant to HER2-targeting therapies, identification of actionable alterations can change second-line (or later) therapy decisions.²

“We generally use NGS to look for additional alterations,” explained Mafalda Oliveira, MD, PhD, from the Vall d'Hebron Institute of Oncology in Barcelona, Spain. “And these are the actionable mutations that we are looking at in…[HR+/HER2–] disease—germline and tumor—are BRCA1 and BRCA2 mutations, PIK3CA mutations, AKT1 mutations, PTEN alterations and ESR1 mutations. And the reason to look for these alterations is because we now have drugs that target each of these alterations.”²

NGS can be performed on tissue or liquid biopsy samples; of which both are often considered based on feasibility, disease site, and how urgently results are needed. Tumor NGS provides a comprehensive baseline profile but is more invasive, lending to less frequent NGS testing and a poorer patient experience. Alternatively, plasma NGS can be repeated over time, allowing for more consistent monitoring of resistance mutations.²

Targeting PIK3CA-Driven Pathways

PIK3CA mutations are most common in HR+/HER2–BC and is reported in approximately 20% to 25% of all cases. Mutations in PIK3CA activate the PI3K/AKT/mTOR pathway, driving tumor growth, endocrine resistance, and disease progression. In HER2-altered BCs, PI3K pathway activation—marked by PIK3CA mutation or loss of PTEN expression—is considered as a key driver of HER2 signaling intrinsic resistance to trastuzumab.^2,4

There are various FDA-approved PIK3CA inhibitors for treatment of HR+/HER2– BC including inavolisib (Itovebi; Genentech), alpelisib (Piqray; Novartis), capivasertib (Truqap; AstraZeneca), and everolimus (Zortress; Novartis Pharmaceuticals).

Beyond the FDA-approved agents, gedatolisib (PF-05212384; Celcuity, Inc), an intravenous dual PI3K/mTOR inhibitor with a broader, more potent suppression across the PI3K–AKT–mTOR axis compared with alpelisib or inavolisib. This allows for a more complete shutdown of the pathway and a potential reduction of feedback reactivation, which can occur with single‑node inhibition.²

The phase 3 VIKTORIA-1 trial (NCT05501886)⁹ evaluated gedatolisib in patients with HR+/HER2–, PIK3CA–wild-type advanced BC who had progressed on prior CDK4/6 inhibitor plus aromatase inhibitor therapy. In this study of 392 patients, the triplet regimen of gedatolisib, palbociclib, and fulvestrant (Faslodex; AstraZeneca) achieved a markedly improved median PFS of 9.3 months, compared with 2 months for fulvestrant alone and 7.4 months for the gedatolisib–fulvestrant doublet.¹⁰

Response rates were also substantially higher with gedatolisib—32% with the triplet versus 1% with fulvestrant alone—and early OS trends favored both gedatolisib-containing arms. Safety findings aligned with known profiles, with low discontinuation rates and manageable AEs; hyperglycemia occurred in less than 12% of patients, with few grade 3 events.¹⁰

Gedatolisib’s benefit appeared independent of duration of prior ET, suggesting it could help in both relatively endocrine‑sensitive and more resistant tumors. In combination therapies, the agent may help delay resistance and extend disease control beyond what CDK4/6 and ET alone achieve.²

The most notable AEs associated with gedatolisib are stomatitis and oral mucositis—a major class effect when mTOR is involved. Primary prophylaxis with steroid-containing mouthwash is strongly recommended. Other toxicities include nausea, diarrhea, hyperglycemia, and neutropenia when used in combination with palbociclib.²

Targeting ESR1 With Next-Generation Endocrine Agents

Another actionable mutation is ESR1, a gene that encodes the estrogen receptor alpha (ERα)—the main estrogen receptor (ER) that binds estrogen to promote driving growth in HR+/HER2– BC. Selective estrogen receptor degraders (SERDs) are an emerging class of ET drugs that bind to ER, block its function, and trigger its degradation. Compared with classic anti‑estrogens like tamoxifen, SERDs not only block ER but also remove it, thereby reducing the amount of ER in the cell.²

Another novel, emerging class of drugs are PROTACs (Proteolysis Targeting Chimeras) which mark proteins for destruction by the cell’s own disposal system. PROTAC molecules are composed of 2 ends joined by a linker: 1 end binds to the target protein (eg, ER) and the other binds to E3 ubiquitin ligase—a cellular “tagging” enzyme—to flag proteins for breakdown in the proteasome.²

SERDs

Elacestrant (Orserdu; Stemline Therapeutics, Inc) is the first oral SERD approved for patients with ESR1-mutant, HR+ mBC whose disease has progressed on prior ET. Its approval was supported by the phase 3 EMERALD trial (NCT03778931),¹¹ in which elacestrant 345 mg daily significantly extended PFS compared with investigator’s choice of fulvestrant or an aromatase inhibitor—improving median PFS from 3.8 months to as long as 9 months in certain subgroups, particularly among patients with prolonged prior CDK4/6 inhibitor exposure.^2,12

Camizestrant (AZD9833; AstraZeneca), another next-generation oral SERD in development, has also shown encouraging activity for patients with HR+ disease. In the phase 2 SERENA-2 trial (NCT04214288),¹³ camizestrant demonstrated superior efficacy to fulvestrant in the second-line metastatic setting, with especially strong responses among patients harboring ESR1 mutations. Phase 3 studies are now evaluating daily doses of 70 mg to 75 mg.^2,12

“Very interestingly, in the subgroup analysis, this benefit was consistent whether the cancer had an ESR1 mutation or did not have an ESR1 mutation,” said Erica Mayer, MD, MPH, from Dana-Farber Cancer Institute in Boston. “And so, this begins to raise this question of combining novel endocrine agents with a targeted agent, which can overcome resistance from crosstalk pathways and may provide the greatest efficacy.”²

In the phase 3 EMBER-3 trial (NCT04975308)¹⁴ evaluating imlunestrant (Inluriyo; Eli Lilly & Co) as both monotherapy and in combination with abemaciclib for HR-positive, HR+/HER2– BC after prior ET, including CDK4/6 inhibitors. The most clinically meaningful finding came from the combination arm: imlunestrant plus abemaciclib substantially extended PFS compared with imlunestrant alone (approximately 5.5 to 9.4 months), with benefit observed regardless of ESR1 mutation status. These results reinforce a growing shift away from endocrine monotherapy toward SERD-based targeted combinations to achieve more durable disease control.

PROTACs

Vepdegestrant (ARV-471; Arvinas, Inc) represents a promising novel endocrine treatment for patients with HR+/HER2– mBC, according to emerging data from the phase 2 VERITAC‑2 trial (NCT05654623).¹⁵ In the trial, patients in the ESR1-mutated subgroup treated with vepdegestrant monotherapy experienced a PFS improvement from about 2 months with fulvestrant to about 5 months with vepdegestrant.

These results are similar in magnitude to the benefit seen with other next‑generation endocrine agents, supporting vepdegestrant as an active ER degrader in the post‑CDK4/6, ESR1‑mutant setting, and an alternative to oral SERDs.

Evolving Treatment Strategies After CDK4/6 Inhibitor Progression

HR+/HER2– mBC after CDK4/6 inhibitor progression remains a highly heterogenous and challenging clinical setting, emphasizing the critical need for effective post-CDK4/6 inhibitor treatment protocols. Emerging clinical trial data—including EMBER-3 and VIKTORIA-1—support oral SERD–based combinations, particularly SERD plus CDK4/6 inhibitor regimens, as offering superior activity to SERD monotherapy in the post-CDK4/6 setting. This represents an evolution in treatment strategy toward multi-targeted endocrine regimens that address resistance mechanisms at multiple signaling nodes.

“I would again propose that the era of endocrine monotherapy for ER‑positive metastatic breast cancer is over,” explained Mayer. “And with rare exception, we should be striving to provide [ET] with targeted partners for our patients, certainly in the post‑CDK4/6 setting, and perhaps in all lines of therapy.”

REFERENCES

1. Gerlach A. Five-year NATALEE data show ribociclib improves outcomes in high-risk HR+/HER2– early breast cancer. Pharmacy Times. October 17, 2025. Accessed December 9, 2025. https://www.pharmacytimes.com/view/five-year-natalee-data-show-ribociclib-improves-outcomes-in-high-risk-hr-her2-early-breast-cancer

2. Tan A, Oliveira M, Mayer E, et al. Educational Session 1: after CDK4/6 inhibitors—advancing treatment for HR+HER2-negative metastatic breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium. December 9-12, 2025. San Antonio, TX

3. Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. March 12, 2021. doi: 10.18632/genesandcancer.211

4. Chen H, Hu X, Wang D, et al. Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: A meta-analysis and bioinformatic analysis of TCGA‑BRCA data. Transl Oncol. August 17, 2023. doi: 10.1016/j.tranon.2023.101738

5. A study evaluating the efficacy and safety of inavolisib + palbociclib + fulvestrant vs placebo + palbociclib + fulvestrant in participants with PIK3CA-Mutant, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (INAVO120). Clinicaltrials.gov. Updated October 3, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT04191499

6. study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). Clinicaltrials.gov. Updated February 13, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT02437318

7. capivasertib+fulvestrant vs placebo+fulvestrant as treatment for locally advanced (inoperable) or metastatic HR+/​HER2- breast cancer (CAPItello-291). Clinicaltrials.gov. Updated October 27, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT04305496

8. Everolimus in combination with exemestane in the treatment of postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole (BOLERO-2). Clinicaltrials.gov. Updated April 2, 2017. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT00863655

9. Gedatolisib plus fulvestrant with or without palbociclib vs standard-of-care for the treatment of patients with advanced or metastatic HR+/​HER2- breast cancer (VIKTORIA-1) (VIKTORIA-1). Clinicaltrials.gov. Updated June 24, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT05501886

10. Gerlach A. Gedatolisib triplet shows significant PFS benefit in HR+/HER2– breast cancer. Pharmacy Times. November 6, 2025. Accessed December 9, 2025. https://www.pharmacytimes.com/view/gedatolisib-triplet-shows-significant-pfs-benefit-in-hr-her2-breast-cancer

11. Phase 3 trial of elacestrant vs. standard of care for the treatment of patients with ER+/​HER2- advanced breast cancer (EMERALD). Updated September 15, 2024. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT03778931

12. Gerlach A. ESR1, PIK3CA, and beyond: Precision therapy advances in HR+ breast cancer. Pharmacy Times. May 30, 2025. Accessed December 9, 2025. https://www.pharmacytimes.com/view/esr1-pik3ca-and-beyond-precision-therapy-advances-in-hr-breast-cancer

13. A study to investigate efficacy and safety with oral AZD9833 compared with intramuscular fulvestrant in post-menopausal women at least 18 years of age with advanced ER-positive HER2 negative breast cancer (SERENA-2). Updated November 20, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT04214288

14. A study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2- advanced breast cancer (EMBER-3). Clinicaltrials.gov. Updated July 11, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT04975308

15. A study to learn about a new medicine called vepdegestrant (ARV-471, PF-07850327) in people who have advanced metastatic breast cancer (VERITAC-2). Updated July 3, 2025. Accessed December 9, 2025. https://clinicaltrials.gov/study/NCT05654623