Six Practice-Informing Breast Cancer Trials From ASCO 2026

Breast cancer research presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting highlighted meaningful advances across early-stage and metastatic settings, with several studies set to influence clinical practice. From next-generation endocrine therapies to antibody-drug conjugates and novel pathway inhibitors, these data highlight a continued shift toward more targeted and individualized treatment strategies.

This summary highlights six key trials that stood out for their potential clinical impact. Across hormone receptor–positive, HER2-positive, and TNBC subtypes, these studies demonstrated improvements in disease control, PFS, and tolerability, while also addressing unmet needs in treatment-resistant and immunotherapy-ineligible populations.

Early-Stage Disease: lidERA Trial of Giredestrant vs Standard Endocrine Therapy

In ER-positive/HER2-negative stage I–III early breast cancer (N = 4170), giredestrant, a next-generation oral selective estrogen receptor degrader and full ER antagonist, demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS) compared with standard-of-care (SOC) endocrine therapy. Premenopausal women receiving giredestrant or an aromatase inhibitor (AI) also received a luteinizing hormone-releasing hormone agonist.

Key findings by menopausal status (~40% premenopausal, ~60% postmenopausal):

• iDFS: Hazard ratio (HR), 0.65 (premenopausal) versus 0.74 (postmenopausal)
• Distant recurrence-free interval: HR, 0.58 versus 0.76, respectively, corresponding to a 42% reduction in risk of metastatic disease in premenopausal and 24% in postmenopausal patients.
• Tolerability: Fewer discontinuations because of adverse events (AEs) with giredestrant compared with AI regardless of menopausal status.
  • Musculoskeletal pain occurred in over half of patients in both arms, but discontinuation for this reason was lower with giredestrant (1.6%) versus AI/tamoxifen (4.5%).

Metastatic Disease: persevERA Trial of Giredestrant Plus Palbociclib vs Letrozole Plus Palbociclib

In 992 patients with previously untreated ER-positive locally advanced or metastatic breast cancer (mBC), giredestrant plus palbociclib was compared with letrozole plus palbociclib. At a median follow-up of 52.2 months (623 investigator-assessed progression-free survival [INV-PFS] events):

• INV-PFS: HR, 0.89 (95% CI, 0.76–1.05; P = 0.16); median 33.1 months versus 28.2 months (Δ 4.9 months)
• Duration of response: 38.5 months versus 30.4 months (HR, 0.80; 95% CI, 0.63–1.01; P = 0.056)

Clinical implication: Giredestrant combined with palbociclib showed a numerical but not statistically significant improvement in INV-PFS over letrozole plus palbociclib.

Post–CDK4/6 Inhibitor Setting: VIKTORIA-1 Study 2

Patients with PIK3CA-mutant ER-positive/HER2-negative advanced breast cancer who progressed on prior CDK4/6i plus AI were randomized 3:3:1 to gedatolisib/palbociclib/fulvestrant (triplet), alpelisib/fulvestrant, or gedatolisib/fulvestrant (doublet).

Gedatolisib is a comprehensive PAM pathway inhibitor targeting all class I PI3K isoforms, mechanistic target of rapamycin complex 1 (mTORC1), and mTORC2.

• Triplet versus alpelisib/fulvestrant: mPFS 11.1 months versus 5.6 months (HR, 0.50; 95% CI, 0.37–0.68; P < 0.0001)
• Doublet versus alpelisib/fulvestrant: mPFS 11.3 months versus 5.6 months (HR, 0.51; 95% CI, 0.33–0.79; P = 0.0013)
• Low rates of treatment discontinuation because of AEs.

Clinical implication: Combined with prior data in PIK3CA wild-type disease, these results position gedatolisib-based combinations as a potential second-line (2L) standard in ER-positive/HER2-negative advanced breast cancer irrespective of PIK3CA mutation status.

Early-Stage HER2-Positive Disease: DESTINY-Breast05 Trial Safety Update of Trastuzumab Deruxtecan

Trastuzumab deruxtecan (T-DXd) previously demonstrated superior efficacy over ado-trastuzumab emtansine in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. The update from ASCO 2026 focused on safety outcomes stratified by risk factors, including patients who received adjuvant radiotherapy.

• Drug-related interstitial lung disease (ILD) rates were generally consistent across global regions, with higher rates observed in Japan and in patients with baseline moderate (versus normal) renal function.
• Both ILD and radiation pneumonitis events were mostly low grade and reversible with protocol-specific management.

Clinical implication: These data further reinforce the manageable safety profile of T-DXd in the post-neoadjuvant HER2-positive early breast cancer setting.

First-Line Metastatic PD-L1–Positive Disease: ASCENT-04 Trial of Sacituzumab Govitecan Plus Pembrolizumab

In previously untreated PD-L1–positive mTNBC, first-line sacituzumab govitecan (SG) plus pembrolizumab was compared with chemotherapy plus pembrolizumab.

• PFS: Median, 11.2 months versus 7.8 months (HR, 0.65; 95% CI, 0.51–0.84; P < 0.001)
• PFS2 (time to progression on next-line therapy or death): Improved with SG plus pembrolizumab, with most chemotherapy/pembrolizumab patients receiving SG as their next-line treatment
• Time to first subsequent therapy: 17.3 months versus 9.8 months
• Overall survival (OS) data remain immature (median follow-up 14 months); 43% of SG/pembrolizumab patients remained on study treatment compared with 23% in the control arm.

Clinical implication: SG plus pembrolizumab as first-line therapy provides clinically meaningful and sustained benefit beyond first progression in PD-L1–positive mTNBC.

First-Line Metastatic Immunotherapy-Ineligible Disease: TROPION-Breast02 Trial of Datopotamab Deruxtecan vs Chemotherapy

In patients with locally advanced or mTNBC not eligible for immunotherapy, first-line datopotamab deruxtecan (Dato-DXd) was compared with investigator’s choice chemotherapy (ICC).

• OS: HR, 0.79 (95% CI, 0.64–0.98; P = 0.029); ≥5-month improvement
• PFS: HR, 0.57 (95% CI, 0.47–0.69; P < 0.0001); ≥5-month improvement
• PFS2: Median, 15.6 months versus 11.8 months (HR, 0.61; 95% CI, 0.50–0.74)
• Time to first and second subsequent therapies were both prolonged with Dato-DXd, with a manageable safety profile.

Clinical implication: These data support Dato-DXd as a new first-line standard for immunotherapy-ineligible locally advanced or mTNBC.