The ELEGANT trial uses a "switch strategy," introducing elicestrin only after 2-5 years of standard therapy. This design pragmatically adapts to the evolving clinical landscape where CDK4/6 inhibitors are now standard initial treatment, ensuring the trial's relevance by testing the drug in a post-CDK4/6 inhibitor setting.
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The ELEGANT trial enrolls all high-risk ER-positive patients, not just those with ESR1 mutations. The rationale is that unlike in metastatic disease, early breast cancer is fundamentally ER-driven. Elicestrin targets both wild-type and mutant ER, making the mutation status less critical for efficacy in this earlier setting.
Positive data from both DESTINY-Breast09 (TDXD-based) and PATINA (CDK4/6i maintenance) create a new dilemma. With similar PFS outcomes, the first-line choice for metastatic HER2+/HR+ patients now hinges on toxicity profiles and patient preference rather than a single efficacy winner.
A patient's time to progression on first-line CDK4/6 inhibitor therapy acts as an informal biomarker. A shorter duration, such as 14 months, is viewed by experts as "not so great" and indicates a degree of underlying endocrine resistance that influences subsequent treatment strategies.
When treating elderly patients (e.g., age 80+) with metastatic breast cancer, clinicians may prioritize quality of life over marginal overall survival gains seen in clinical trials. This justifies using a better-tolerated CDK4/6 inhibitor like palbociclib, even though ribociclib has demonstrated a statistical survival benefit, especially when patients have comorbidities or a preference for fewer side effects.
Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.
While the Lidera trial showed a benefit for the oral SERD giredestrant in the adjuvant setting, experts advise caution before changing practice. The trial's control arm (standard endocrine therapy) does not reflect the current standard of care for high-risk patients, which now includes CDK4/6 inhibitors, making a direct comparison difficult.
Three major trials (RIGHT Choice, PADMA, OMBRE) definitively show that starting with a CDK4/6 inhibitor plus endocrine therapy is superior to upfront chemotherapy for newly diagnosed, symptomatic metastatic breast cancer. This approach provides better progression-free survival without the toxicity of chemotherapy and, critically, does not result in a slower time to response.
For high-risk, HR+ patients with germline BRCA mutations, data suggest they derive less benefit from CDK4/6 inhibitors. A practical approach is to give one year of the PARP inhibitor olaparib first, followed by a CDK4/6 inhibitor, capitalizing on the delayed initiation allowance in major trials.
Data from the MONARCH-E and NATALY trials show that the benefit of adjuvant CDK4/6 inhibitors like abemaciclib and ribociclib persists and even increases after patients complete their 2-3 year treatment course. This sustained "carryover effect" suggests a lasting impact on disease biology rather than just temporary suppression.
Using a second CDK4/6 inhibitor after progression on a first showed disappointing results in trials like post-MONARCH. However, the EMBER-3 trial's success, combining abemaciclib with the novel SERD imlunestrant, demonstrated robust efficacy. This suggests the choice of endocrine partner is the critical factor for making this sequencing strategy viable.
