3 Trials Refine Endocrine, HER2-Targeted Therapies at SABCS

Several clinical trials presented during the 2025 San Antonio Breast Cancer Symposium in Texas provided practice-changing data across the metastatic and early-stage breast cancer settings. In particular, findings from the lidERA (NCT04961996),¹ HER2CLIMB-05 (NCT05132582),² and MONALEESA-3 (NCT02422615)³ trials provide clinicians with refined approaches and emphasize the importance of potent, manageable, and sustained therapeutic regimens.

Although these trials address different molecular subtypes, ie, patients with HER2-positive or hormone receptor–positive/HER2-negative disease, the focus remains on maintenance, improved quality of life, and smarter, more effective regimens.

Giredestrant

The novel oral selective estrogen receptor (ER) degrader giredestrant significantly reduced the risk of invasive disease recurrence or death compared with standard of care (SOC) endocrine therapy in the phase 3 lidERA trial for patients with early breast cancer, potentially offering a new adjuvant treatment option.¹

At a median follow-up of 32.6 months, giredestrant demonstrated a 30% reduction in the risk of invasive disease recurrence or death compared with physician’s choice of tamoxifen or an aromatase inhibitor (HR, 0.70; 95% CI, 0.57–0.87; P =.0014).¹ The 3-year invasive disease–free survival (IDFS) rate was 92.4% for giredestrant vs 89.6% for SOC, an absolute improvement of approximately 3%.¹

“The 3-year [IDFS] was 92.4% for the treatment arm vs 89.6% for the control arm,” Aditya L. Bardia, MD, MPH, said during the presentation of the data. “That translates to an absolute improvement of about 3% with giredestrant.” Bardia is a professor of medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA. He currently serves as program director of breast medical oncology and director of translational research integration at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles.

Comparing giredestrant with other estrogen therapy, giredestrant was superior to aromatase inhibitors (HR, 0.73; 95% CI, 0.58-0.92) and tamoxifen (HR, 0.53; 95% CI, 0.35-0.80).¹

Overall, patients with ER-positive, HER2-negative disease account for more than 70% of early breast cancer cases, with tamoxifen or aromatase inhibitors being the mainstay of treatment. Although early breast cancer is treated with curative intent, about 25% of patients develop recurrence within 5 years of estrogen therapy.⁴ Safety and tolerability are also factors and lead to early treatment discontinuation, which also increases the risk of recurrence.

“These limitations underscore the need for more effective and better-tolerated adjuvant estrogen therapies,” Bardia said.

Study Design

The global lidERA trial enrolled 4170 patients with stage I to III, ER-positive, HER2-negative early breast cancer who had undergone surgery within the prior 12 months. Patients were randomly assigned 1:1 to receive adjuvant giredestrant (30 mg orally daily; n = 2084) or SOC endocrine therapy (n = 2086), stratified by risk, region, prior chemotherapy, and menopausal status. The primary end point was IDFS, and secondary end points included DFS, distant recurrence-free interval, IDFS, overall survival (OS), and safety.¹

As of the data cutoff of August 8, 2025, OS was 32.4 months in the giredestrant arm and 32.3 months in the SOC estrogen therapy arm (HR, 0.79; 95% CI, 0.56-1.12; P = .19). Regarding OS, Bardia noted that “the results are immature, but at this time, a positive trend in OS was observed.”

Safety Data

Bardia reported that the most adverse events (AEs) were arthralgias, followed by menopausal symptoms such as hot flashes. Treatment discontinuation due to arthralgia was 1.6% in the giredestrant arm vs 3.7% in the SOC endocrine therapy arm. “In the study, patients were allowed to switch aromatase inhibitors,” Bardia noted. “If a patient experienced AEs secondary to letrozole, they could switch to exemestane or anastrozole or tamoxifen.”

Bradycardia was higher among patients in the treatment arm; 10.5% of cases were grade 1 and 0.7% were grade 2. There were no grade 3 or grade 4 cases of bradycardia.

“Grade 1 was asymptomatic and did not lead to treatment discontinuation or hold. This AE was identified during routine monitoring,” Bardia said.

Conversely, rates of grade 3/4 venous thromboembolic events were higher in the SOC arm.

“Since the approval of aromatase inhibitors in 2000, after about 25 years, lidERA is the first trial that has demonstrated benefit with the novel endocrine agent giredestrant in breast cancer,” Bardia said. “The safety profile for the agent is favorable and the discontinuation rate was numerically lower for giredestrant compared with SOC [endocrine therapy]. Overall, these data support giredestrant as a new potential standard endocrine option for patients with [hormone receptor]–positive breast cancer,” Bardia concluded.

HER2CLIMB-05

The addition of oral tucatinib (Tukysa) to maintenance trastuzumab (Herceptin) and pertuzumab (Perjeta; HP) significantly improved progression-free survival (PFS) compared with HP alone in patients with HER2-positive metastatic breast cancer who had not progressed on first-line docetaxel-based induction, according to results from the phase 3 HER2CLIMB-05 trial.²

A preliminary look at the data, which were presented at the 2025 San Antonio Breast Cancer Symposium with median follow-up of approximately 23 months, demonstrated that the median PFS was 24.9 months (95% CI, 21.3-not available [NA]) with tucatinib/HP (n = 326) vs 16.3 months (95% CI, 12.6-18.7) with placebo/HP (n = 328; HR, 0.641; 95% CI, 0.514-0.799; P < .0001).² Top-line results from the HER2CLIMB-05 trial were first announced in October 2025, indicating that the study had met its primary end point.⁵

The PFS benefit with tucatinib also extended across all prespecified patient subgroups, which looked at diagnosis (de novo or recurrent), hormone receptor status (negative or positive), brain metastases at baseline (yes or no), prior anti-HER2 therapy (yes or no), best response to trihexyphenidyl (THP) induction (complete response [CR]/partial response [PR] or stable disease/non–CR/PR), disease type (visceral or nonvisceral), ECOG performance status (0 or 1), region (North America, Europe, Asia-Pacific, or rest of the world), age in years (< 65 or ≥ 65), and race (White, Asian, or other).

“HER2CLIMB-05 has demonstrated that the addition of tucatinib to HP represents an enhanced frontline maintenance therapy option for patients with HER2-positive metastatic breast cancer, providing an opportunity to prolong time to disease progression and time off chemotherapy,” Erika Hamilton, MD, lead study author and director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, said during a news briefing.

HER2CLIMB-05 Background

First-line treatment for patients with HER2-positive metastatic breast cancer typically includes taxane-based chemotherapy with HP, followed by HP maintenance, but disease progression often prevents patients from reaching second-line therapy.

Prior data from the pivotal phase 2 HER2CLIMB trial (NCT02614794) showed that adding tucatinib to capecitabine and trastuzumab improved PFS and OS even in heavily pretreated populations, including those with brain metastases. HER2CLIMB-05 was launched to evaluate whether incorporating tucatinib into first-line maintenance with HP could further enhance outcomes by intensifying both extracellular and intracellular HER2 targeting.

HER2CLIMB-05 is a randomized, double-blind, placebo-controlled, international, phase 3 trial that enrolled patients with centrally confirmed HER2-positive metastatic breast cancer with no evidence of progression after 4 to 8 cycles of THP, no or asymptomatic brain metastases confirmed by contrast-enhanced MRI at screening, and an ECOG performance status of 0 or 1.

Patients were randomly assigned to receive 300 mg of tucatinib twice daily (n = 326) or matched placebo (n = 328), both in combination with HP once every 21 days with or without endocrine therapy. Trastuzumab was administered intravenously (IV) at 6 mg/kg or 600 mg subcutaneously (SC), and pertuzumab was given at 420 mg IV. The fixed-dose SC combination of 600 mg of trastuzumab, 600 mg of pertuzumab, and 20,000 units of hyaluronidase-zzxf (Phesgo) was also allowed.

Therapy was continued until unacceptable toxicity, disease progression, consent withdrawal, or study closure. Crossover was prohibited.

The primary end point was investigator-assessed PFS per RECIST 1.1 criteria. Secondary end points were OS, PFS per blinded independent central review, central nervous system PFS, safety, health-related quality of life, and pharmacokinetics.

Patients were stratified by diagnosis (de novo or recurrent), hormone receptor status (positive or negative), and presence or history of brain metastases (yes or no).

Efficacy Data

When PFS benefit was stratified by hormone receptor status, investigators noted greater benefit in the hormone receptor–negative population, although the benefit was still observed in the hormone receptor–positive population.

In the former cohort, the median PFS was 24.9 months (95% CI, 19.4-NA) with tucatinib (n = 158) vs 12.6 months (95% CI, 9.4-16.8) with placebo (n = 152; HR, 0.554; 95% CI, 0.403-0.761; P =.0002). In the latter cohort, the median PFS in the tucatinib (n = 168) and placebo (n = 176) arms was 25.0 months (95% CI, 16.5-NA) and 18.1 months (95% CI, 13.0-20.8), respectively (HR, 0.725; 95% CI, 0.535-0.983; P =.0389).

Assessment of the key secondary end point of the trial pointed to a numerical trend for OS improvement in the tucatinib arm (HR, 0.539; 95% CI, 0.303-0.957; P =.0320).

Safety Profile

“The tucatinib and HP combination showed a manageable safety profile, with diarrhea, nausea, and elevated liver enzymes, mostly of low grade, being the most common [AEs],” Hamilton reported.

Safety was evaluated in all patients who were randomly assigned and received at least 1 dose of study therapy. Notably, if a patient discontinued trastuzumab or pertuzumab, they were required to discontinue both agents.

The median duration of tucatinib (n = 326) and placebo (n = 324) therapy was 17.1 months (range, 0.4-36.5) and 15.5 months (95% CI, 0.5-41.3), respectively. Treatment-emergent AEs (TEAEs) occurred in 99.1% and 96.6% of patients in the tucatinib and placebo arms, respectively. In the tucatinib arm, the rates of grade 3 or greater TEAEs, serious TEAEs, and TEAEs leading to death were 43.2%, 16.9%, and 0.3%, respectively. These respective rates in the placebo arm were 24.4%, 8.0%, and 0.3%.

TEAEs leading to treatment discontinuation occurred in 13.8% and 4.6% of patients in the tucatinib and placebo arms, respectively. The rates of discontinuation for tucatinib/placebo, individually administered HP, or fixed-dose HP were 13.5%, 0.6%, and 2.8%, respectively, in the tucatinib arm and 2.2%, 1.5%, and 1.2% in the placebo arm.

The most common TEAEs leading to tucatinib or placebo discontinuation were hepatic events (tucatinib, 7.7%; placebo, 0%) and diarrhea (1.5%; 0.9%). Dose modification because of a TEAE was reported in 55.8% and 34.6% of patients in the tucatinib and placebo arms, respectively. TEAEs leading to tucatinib dose hold or reduction occurred in 49.4% and 29.1% of patients, respectively; these respective rates for placebo were 25.3% and 11.1% in the placebo arm.

MONALEESA-3

Exploratory findings from the phase 3 MONALEESA-3 trial (NCT02422615) highlight the benefit of ribociclib (Kisqali) plus fulvestrant (Faslodex) for patients with hormone receptor–positive, HER2-negative advanced breast cancer who have invasive lobular carcinoma (ILC), a distinct histologic subtype that accounts for 10% to 15% of breast cancer cases.³ The subgroup analysis confirms the regimen’s efficacy in ILC, a unique subpopulation.

Improved Survival

The original MONALEESA-3 study demonstrated a significant survival advantage for ribociclib plus fulvestrant vs placebo plus fulvestrant in postmenopausal patients receiving first-line or second-line treatment. With longer follow-up beyond 56 months, this OS benefit remained durable.

At the primary analysis, median PFS improved from 12.8 months in the placebo arm to 20.5 months with ribociclib (HR, 0.59; 95% CI, 0.48-0.73; P < .001), and a statistically significant OS benefit emerged at the final analysis (HR, 0.72; 95% CI, 0.57-0.92).³

Given the unique biology, metastatic patterns, and treatment responses associated with ILC, investigators conducted a subgroup analysis to better understand outcomes among these patients within MONALEESA-3.³

Study Design and Subgroup Characteristics

Among the 726 patients enrolled, 120 (16.5%) had ILC, with 77 randomly assigned to receive ribociclib plus fulvestrant and 43 to receive placebo plus fulvestrant. The subgroup mirrored the broader study population, with a median age of 63 years and balanced baseline characteristics across treatment arms.

Most patients (more than 80%) had relapsed over 12 months after completing prior adjuvant or neoadjuvant endocrine therapy, and a majority had bone metastases. Visceral metastases were present in about 45% of patients with ILC.³

Improved PFS and OS With Ribociclib

Outcomes were also evaluated in the first-line setting. Patients with ILC experienced a substantial PFS advantage with ribociclib. Median PFS was 20.5 months with ribociclib plus fulvestrant compared with 9.4 months with placebo plus fulvestrant (HR, 0.56; 95% CI, 0.37-0.86).³

In the first-line setting, patients with ILC receiving ribociclib plus fulvestrant showed an even longer median PFS of 26.3 months, compared with 18.1 months for those receiving placebo, although this comparison did not reach statistical significance given the small sample size (HR, 0.78; 95% CI, 0.39-1.59).³

OS outcomes were similarly favorable. Median OS for patients with ILC treated with ribociclib plus fulvestrant reached 51.2 months, compared with 30.8 months for placebo (HR, 0.62). Among first-line patients, OS extended to 59.6 months with ribociclib vs 40.0 months with placebo.³

These findings indicate that the survival benefit seen in the overall MONALEESA-3 population is preserved—and potentially magnified—in patients with the ILC subtype.³

Safety Profile

Ribociclib was well tolerated in the ILC subgroup. Rates of AEs, including neutropenia and liver enzyme elevations, were comparable to those observed in the overall trial population. No new safety signals emerged in the ILC cohort or the first-line subgroup.³

This exploratory analysis suggests that ribociclib plus fulvestrant provides meaningful PFS and OS benefits for patients with hormone receptor–positive/HER2-negative ILC, reinforcing its role as an important treatment option in both first- and second-line settings.

REFERENCES

1. Bardia AL. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: results from the global phase 3 lidERA breast cancer trial. Presented at: San Antonio Breast Cancer Symposium 2025; December 9-12, 2025; San Antonio, TX. Abstract GS1-10.

2. Hamilton E, Curigliano G, Martin M, et al. HER2CLIMB-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium 2025; December 9-12, 2025; San Antonio, TX. Abstract GS1-01.

3. De Laurentiis M, Mouabbi J, Im S, et al. Progression-free survival (PFS) and overall survival (OS) results from the phase 3 MONALEESA-3 trial of postmenopausal patients with hormone receptor-positive (HR+)/HER2-negative (HER2−) advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL): a subgroup analysis of patients with invasive lobular carcinoma (ILC). Presented at: San Antonio Breast Cancer Symposium 2025; December 9-12, 2025; San Antonio, TX. Abstract PS1-10-27.

4. Sheffield KM, Peachey JR, Method M, et al. A real-world US study of recurrence risks using combined clinicopathological features in HR-positive, HER2-negative early breast cancer. Future Oncol. 2022;18(21):2667-2682. doi:10.2217/fon-2022-0310

5. Tukysa combination significantly improves progression-free survival as first-line maintenance in HER2+ metastatic breast cancer in HER2CLIMB-05 trial. News release. Pfizer. October 14, 2025. Accessed January 13, 2026. https://tinyurl.com/yjytdvw4