Elacestrant Real-World Outcomes Exceed Expectations

A recent study investigated the real-world effectiveness of elacestrant, a novel oral selective estrogen receptor degrader, in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. The study utilized data from the large clinical-genomic GuardantINFORM database. All the patients had ESR1 mutations detected in their circulating tumor DNA and received elacestrant for treatment.

Real-world treatment outcomes measured in this study included real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT). The findings revealed that both rwTTD and rwTTNT exceeded the progression-free survival reported in the EMERALD trial, which was the pivotal clinical trial that led to the approval of elacestrant. In this real-world study, of the 742 evaluable patients, the median rwTTD and rwTTNT were 4.6 months and 6.43 months, respectively. The contrast between the real-world and clinical trial results suggests that the effectiveness of elacestrant in everyday clinical practice may surpass its performance measured in controlled trial settings.

The study also investigated the impact of several factors on treatment outcomes, including specific ESR1 mutations (D538G vs Y537S and Y537S vs ESR1m), prior exposure to endocrine therapy such as an aromatase inhibitor or fulvestrant, and the line of therapy in which elacestrant was used (second vs third vs fourth+). There were no significant differences in rwTTD or rwTTNT based on these variables, suggesting that elacestrant provides consistent benefit across diverse patient subgroups, regardless of the specific ESR1 mutation they harbor or their prior treatment history.

However, 2 significant factors emerged that were associated with reduced real-world outcomes. The study revealed that patients with >4 ESR1 mutations had a statistically significantly worse rwTTD compared with patients with only 1 ESR1 mutation (3.73 months vs 5.27 months; hazard ratio, 1.70; 95% confidence interval [CI], 1.23-2.33). While patients with >4 ESR1 mutations also demonstrated shorter rwTTNT, this difference did not reach statistical significance. The presence of oncogenic mutations in the PI3K pathway was also found to be a significant factor associated with shorter treatment duration. Patients with oncogenic PI3K pathway mutations exhibited significantly worse rwTTD and rwTTNT statistically compared with patients without these mutations (rwTTD: 3.97 months vs 5.27 months; hazard ratio, 1.55; 95% CI, 1.25-1.93; rwTTNT: 4.60 months vs 7.57 months; hazard ratio, 1.58; 95% CI, 1.24-2.00). These observations emphasize a potential correlation between complex ESR1 polyclonality and a decreased responsiveness to endocrine therapy, and the need to consider PI3K pathway alterations when making treatment decisions for advanced breast cancer patients.

These findings have substantial implications for the management of advanced breast cancer. The robust real-world outcomes observed with elacestrant strengthen its position as a valuable endocrine therapy option for patients with ESR1 mutations. In addition, the identification of factors associated with poorer outcomes, such as multiple ESR1 mutations and PI3K pathway alterations, paves the way for more personalized treatment strategies. The researchers suggest that further biomarker analysis may help optimize therapy selection, including the potential use of combination therapy or tailored drug sequencing, particularly in patients who have previously received CDK4/6 inhibitors. This highlights the importance of precision medicine in oncology, where treatment decisions are individualized based on the unique molecular characteristics of a patient’s tumor.

Source

Lloyd M, et al. Impact of prior treatment, ESR1 mutational (ESR1m) landscape, and co-occurring PI3K pathway status on real-world (RW) elacestrant outcomes in patients (pts) with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer (aBC). Presented at: San Antonio Breast Cancer Symposium. December 10, 2024; San Antonio, TX. Abstract SESS-2133.