Overview of positive phase II and III randomized clinical trials with ET-based therapy following progression on CDK4/6i.
| Trial name (intervention, if multiple arms) | Phase | Primary endpoint(s) | Biomarker (% of patients with biomarker) | Pretreatment history (% of patients) | Intervention | Control | PFS in ITT [HR (95% CI)2,P-value] | PFS in biomarker-defined group1 [HR (95% CI)2,P-value)] | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| ≥ 2 ETs3 | CDK4/6i | ChT3 | Fulv | ||||||||
| EMERALD [41] | III | PFS in ITT, PFS in ESR1m | ESR1m (48) | 43.4 | Mand. | 22.2 | 30.4 | Elacestrant | Fulvestrant/AI | 0.70 (0.55−0.88), P = 0.002 | 0.55 (0.39−0.77), P < 0.001 |
| SERENA-2 [44] (Camizestrant 75 mg) | II | PFS for each Camizestrant dose level | NA | Excl. | 51 | 23.8 | Excl. | Camizestrant (75 mg) | Fulvestrant | 0.59 (0.42−0.82)4, P = 0.017 | NA |
| EMBER-3 [46, 47] (Imlunestrant vs. IC ET) | III | PFS in ITT; PFS in ESR1m | ESR1m (38.7) | Excl. | 58.1 | Excl. | Excl. | Imlunestrant | Fulvestrant/AI | 0.89 (0.75−1.05), P = 0.167 | 0.62 (0.47−0.82), P < 0.001 |
| EMBER-3 [46, 47] (Imlunestrant, Abemaciclib vs. Imlunestrant) | III | PFS in ITT | NA | Excl. | 65.5 | Excl. | Excl. | ImlunestrantAbemaciclib | Imlunestrant | 0.59 (0.47−0.74), P < 0.001 | NA |
| VERITAC-2 [52] | III | PFS in ITT, PFS in ESR1m | ESR1m (43.3) | NR5 | Mand. | Excl. | Excl. | Vepdegestrant | Fulvestrant | 0.83 (0.69−1.01), P = 0.07 | 0.58 (0.43−0.78), P < 0.001 |
| MAINTAIN [59] | II | PFS in ITT | NA | 18.5 | Mand. | 9.2 | NR | Switched ET (Fulvestrant/AI)Ribociclib | Switched ET (Fulvestrant/AI)Placebo | 0.57 (0.39−0.85), P = 0.006 | NA |
| postMONARCH [60] | III | PFS in ITT | NA | Excl. | Mand. | Excl. | Excl. | FulvestrantAbemaciclib | FulvestrantPlacebo | 0.73 (0.57−0.95), P = 0.017 | NA |
| CAPItello-291 [82] | III | PFS in ITT, PFS in AKT pathway-altered6 | AKT pathway-altered6 (40.8) | 10.7 | 69.1 | 18.2 | Excl. | FulvestrantCapivasertib | FulvestrantPlacebo | 0.60 (0.51−0.71), P < 0.001 | 0.50 (0.38−0.65), P < 0.001 |
| VIKTORIA-1 [86] (Fulvestrant, Gedatolisib, Palbociclib vs. Fulvestrant) | III | PFS in PIK3CA-WT = ITT | PIK3CA-WT (100) | 10.3 | Mand. | Excl. | NR5 | FulvestrantGedatolisibPalbociclib | Fulvestrant | 0.24 (0.17−0.35), P < 0.001 | Identical to ITT |
| VIKTORIA-1 [86] (Gedatolisib, Fulvestrant vs. Fulvestrant) | III | PFS in PIK3CA-WT = ITT | PIK3CA-WT (100) | 10.3 | Mand. | Excl. | NR5 | FulvestrantGedatolisib | Fulvestrant | 0.33 (0.24−0.48), P < 0.001 | Identical to ITT |
| SERENA-6 [45] | III | PFS in ESR1m = ITT | ESR1m (100) | Excl. | Mand. | 5.4 | Excl. | CamizestrantPalbociclib/Ribociclib or Abemaciclib | AIPalbociclib/Ribociclib or Abemaciclib | 0.44 (0.31−0.60), P < 0.001 | Identical to ITT |
| PADA-1 [57] | III | PFS in ESR1m = ITT | ESR1m (100) | Excl. | Mand. | Excl. | Excl. | FulvestrantPalbociclib | AIPalbociclib | 0.61 (0.43–0.86), P = 0.004 | Identical to ITT |
Only trials with full publication are included. 1 Only reported where efficacy in biomarker-defined population was a primary endpoint; 2 unless otherwise specified; 3 in the advanced setting; 4 90% CI; 5 inclusion possible; 6 molecular alterations in PIK3CA, AKT1, or PTEN. AI: aromatase inhibitor; CDK4/6i: CDK4/6 inhibitor; ChT: chemotherapy; CI: confidence interval; ESR1m: ESR1-mutated; ET: endocrine therapy; Excl.: excluded; Fulv: fulvestrant; HR: hazard ratio; ITT: intention-to-treat; Mand.: mandatory; NA: not applicable; NR: not reported; PFS: progression-free survival; IC ET: investigator's choice of ET; WT: wild-type.
During the preparation of this work, the authors used Claude (Anthropic, Opus 4.8) and ChatGPT (OpenAI, GPT-5.3) for language refinement, improvement of readability, and translation of selected expressions. After using the tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
AMH: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. RB: Conceptualization, Investigation, Supervision, Visualization, Writing—original draft, Writing—review & editing. Both authors read and approved the submitted version.
AMH received travel support from Janssen and Amgen. RB received honoraria from H+O Health Communications, Medtis, Novartis, AstraZeneca, Impulze, Janssen, Silamed, Daiichi-Sankyo, Gilead, Stemline Menarini, MSD, OncoPulse; research funding from Gilead; travel support from Daiichi-Sankyo, Astra Zeneca, Servier and Roche; is a mentee in the ENDEAVOUR-Breast program; his wife is employed by CSL Behring AG; and he is listed on a patent application (provisional application no. 63/503,528) submitted to Massachusetts General Hospital.
Not applicable.
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This study received Institutional Funding from the Department of Medical Oncology and the Medical Faculty of the University of Bern. The funders had no role in the conception and conduct of the review, decision to publish, or preparation of the manuscript.
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