Clinical trials of oral SERDs and ctDNA-guided switching strategies in ESR1-mutant ER+/HER2– advanced breast cancer.
| Clinical trial | Agent | Population | Intervention arm | Comparator arm | Median PFS (ESR1-mut) | HR (95% CI) | Key findings | References |
|---|---|---|---|---|---|---|---|---|
| Classical trials: testing at progression | ||||||||
| EMERALD | Elacestrant | Post-CDK4/6i progression; ER+/HER2– MBC | Elacestrant | SOC ET (fulvestrant or AI) | 3.6 vs. 1.9 months | 0.41 (0.26–0.63) | First FDA-approved oral SERD for ESR1-mut; benefit enriched with ≥ 12 months prior CDK4/6i (8.6 vs. 1.9 months) | [18] |
| EMBER-3 | Imlunestrant | Post-AI ± CDK4/6i | Imlunestrant monotherapy orimlunestrant + abemaciclib | SOC ET (fulvestrant or exemestane) | 10.9 vs. 5.5 months (imlunestrant–abemaciclib vs. imlunestran) | 0.59 (0.47–0.74) | mOS 34.5 vs. 23.1 months (HR 0.60) in ESR1-mut; combination with abemaciclib improved PFS regardless of ESR1 status | [67] |
| SERENA-2 (phase 2,non-registrational) | Camizestrant | Post-ET progression | Camizestrant (75 mg or 150 mg) | Fulvestrant | 6.3 vs. 2.2 months | 0.55 (0.33–0.91) | Phase 2: both 75 mg and 150 mg doses superior to fulvestrant; supported dose selection for SERENA-6 | [16, 72] |
| VERITAC-2 | Vepdegestrant | Post-CDK4/6i progression | Vepdegestrant 200 mg daily (oral) | Fulvestrant 500 mg IM | 5.0 vs. 2.1 months | 0.58 (0.43–0.78) | First phase 3 PROTAC ER degrader trial; primary endpoint met in ESR1-mut population only; ORR 18.6% vs. 4.0%; NDA submitted to FDA | [68] |
| persevERA | Giredestrant+ palbociclib | Treatment-naïve, first-line;ER+/HER2–– LA/MBC | Giredestrant + palbociclib | Letrozole + palbociclib | Not reported | Not reported | Negative trial; numerical but not statistically significant PFS improvement in ITT population; ESR1-mut subgroup data and full results pending presentation | NCT04546009 |
| Interception trials: ctDNA-guided switching ahead of progression | ||||||||
| SERENA-6 | Camizestrant switch(double-blind,placebo-controlled) | ESR1 emergence during first-line therapy AI + CDK4/6i; no clinical/radiologic progression | Camizestrant 75 mg + CDK4/6i + placebo for AI | Continue AI + CDK4/6i + placebo for camizestrant | 16.0 vs. 9.2 months | 0.44 (0.31–0.60) | First global registrational ctDNA-guided switching trial; only double-blind, placebo-controlled interception trial; 56% relative reduction in progression/death risk | [24] |
| PADA-1 | Fulvestrant switch | ESR1 emergence during first-line therapy AI + palbociclib; no clinical/radiologic progression | Switch to fulvestrant + palbociclib | Continue AI + palbociclib | 11.9 vs. 5.7 months (fulvestrant and palbociclib group vs. AI and palbociclib group) | 0.61 (0.43–0.86) | Proof-of-concept for ctDNA-guided switching; first trial to demonstrate PFS benefit from early therapy switch guided by liquid biopsy | [13] |
AI: aromatase inhibitor; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; ctDNA: circulating tumor DNA; ER: estrogen receptor; ET: endocrine therapy; FDA: Food and Drug Administration; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; IM: intramuscular; ITT: intent-to-treat; LA/MBC: locally advanced/metastatic breast cancer; mOS: median overall survival; NDA: new drug application; ORR: objective response rate; PFS: progression-free survival; PROTAC: proteolysis-targeting chimera; SERD: selective estrogen receptor degrader; SOC: standard of care.