Gal‐Yam, Einav Nili

Abstract Background: PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III trial comparing two years of the CDK4/6 inhibitor palbociclib combined with the physician’s choice of adjuvant endocrine therapy, versus endocrine therapy alone for patients with Stage II-III hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Molecular residual disease (MRD) detection via circulating tumor DNA (ctDNA) testing was a predefined biomarker analysis to identify patients at highest risk of recurrence. Methods: PALLAS participants with available tumor block, at least a baseline (pre-study treatment) plasma sample, and either whole blood or buffy coat were randomly selected from the overall study population. Plasma samples on cycle 1 day 1 (C1D1), cycle 6 day 1 (C6D1), and at the end of treatment (EOT) were collected, processed, and stored. Nucleic acids were extracted from primary tumor tissue or, when primary tissue was insufficient, from post-neoadjuvant tumor tissue, provided the sample had sufficient material and tumor cellularity (>25 mm2 tissue area with ≥20% tumor nuclei). Data from next generation sequencing of tumor tissue and matched normal DNA were used to create a personalized ctDNA SignateraTM assay (Natera, Inc.) for MRD assessment in the peripheral blood. ctDNA was reported as mean tumor molecules/mL (MTM/mL) of plasma. The primary endpoint was distant recurrence-free interval (DRFI) based on ctDNA status. Cox Proportional Hazards models were used to evaluate prognosis and predictive interactions. To minimize bias, the biorepository and laboratory teams were blinded to participant identity. Results: In total, 1280 participants were randomly selected for inclusion in this preplanned ctDNA sub-study. WES and WGS are being conducted on tissue, and Signatera results will be generated. Results for association of MRD status (positive/negative) and MTM/mL with DRFI in the context of 7 year median follow up of this study cohort will be reported. Conclusions: The planned analysis is ongoing and the presented work will provide data from the first randomized phase 3 adjuvant study in HR+/HER2- breast cancer to report MRD status by treatment arm. Citation Format: H. A. Parsons, K. Ballman, E. Heitzer, M. Watson, M. Balic, D. Hlauschek, D. Renner, E. Kalashnikova, G. Steger, J. M. Balko, Y. Novik, M. Martin, A. A. Rodriguez, Z. Dayao, A. Chan, E. Nili Gal-Yam, M. C. Liu, C. Isaacs, M. Los, M. Gil Gil, B. Felder, C. Denkert, P. Fasching, F. Liu, T. O'Donnell, E. L. Mayer, M. Gnant, W. F. Symmans, A. DeMichele. Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib in the PALLAS trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF3-04.

Abstract Background: Most patients with estrogen receptor-positive (ER+), metastatic breast cancer (mBC) treated with endocrine therapy (ET) will ultimately develop resistance. A large unmet need exists especially when resistance occurs following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), which is potentially driven by a mutation in the ERα-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. In the ELAINE 1 trial, LAS monotherapy provided numerically greater progression-free survival (PFS, median 5.6 mos vs 3.7 mos; HR: 0.669 [95% CI, 0.445‒1.125], P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) compared with the ER degrader fulvestrant (fulv), with a favorable safety profile (Goetz MP et al. Ann Oncol 2023;34:1141‒51). The single-arm, ELAINE 2 trial showed that LAS combined with abemaciclib (Abema) was well tolerated with a median PFS of ∼13 mos, ORR of 56%, and CBR of 66% (Damodaran S et al. Ann Oncol 2023;34:1131‒40). The phase 3, registrational, ELAINE 3 trial was initiated based on these promising earlier-phase data. Recent results from postMONARCH confirmed superior efficacy of fulv/Abema over fulv/placebo (mPFS 6.0 mos vs 5.3 mos, HR 0.73 [0.57‒0.95], nominal P-value 0.017) in non-biomarker‒selected, mBC patients after progression on a prior CDK4/6i and aromatase inhibitor (AI), with similar HR in an ESR1-mutated cohort (Kalinsky K et al. J Clin Oncol 2025;43:1101‒12). Additionally, recent data from EMBER-3 demonstrated meaningful PFS with a novel ET combined with abemaciclib after progression on AI/CDK4/6i (Jhaveri KL et al. N Engl J Med 2025;392:1189‒202). The ELAINE 3, global trial will compare LAS/Abema with fulv/Abema in a post-CDK4/6i, ESR1-mutation‒selected, mBC population. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Patients are being enrolled at approximately 152 sites in 13 countries (Australia, Belgium, Canada, China, France, Italy, Israel, Poland, Romania, Spain, Taiwan, United Kingdom, United States). Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an AI plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM (days 1, 15, and 29, then once monthly) plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS per RESIST 1.1 by blinded independent central review (BICR); key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Safety, time to cytotoxic chemotherapy, and quality of life (including vaginal health) will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test with an expected PFS hazard ratio of 0.68 at final analysis. Enrollment is currently ongoing to meet the target sample size of 500 patients. Citation Format: M. P. Goetz, S. A. Wander, T. Bachelot, G. Curigliano, A. de Nonneville, E. N. Gal-Yam, K. Jhaveri, S. L. Sammons, S. Shen, C. J. Twelves, G. Gasper, P. V. Plourde, D. J. Portman, S. Damodaran. Open-label, randomized, multicenter, phase 3, ELAINE 3 study of the efficacy and safety of lasofoxifene plus abemaciclib for treating ER+/HER2-, locally advanced or metastatic breast cancer with an ESR1 mutation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-30.

TPS1127 Background: Patients with estrogen receptor-positive (ER+) metastatic breast cancer (mBC) may develop resistance to endocrine therapy (ET), particularly following treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), potentially driven by a mutation in the ERa-coding gene, ESR1. Lasofoxifene (LAS), an oral, next-generation ET and ER breast antagonist, was evaluated in two phase 2 studies of women with ER+/HER2- mBC and an ESR1 mutation who had disease progression on previous ET and CDK4/6i. The ELAINE 1 trial showed numerically greater progression-free survival (PFS, median ~6 vs 4 mos; P=0.138), objective response rate (ORR, 13% vs 3%; P=0.124), and clinical benefit rate (CBR, 37% vs 22%; P=0.117) with LAS monotherapy versus the ER degrader fulvestrant (fulv), with a favorable safety profile (1). The single-arm, ELAINE 2 trial demonstrated that LAS plus abemaciclib (Abema) was well tolerated with a median PFS of ~13 mos, ORR of 56%, and CBR of 66% (2). Based on these data, the phase 3, registrational, ELAINE 3 trial was initiated. Methods: ELAINE 3 (NCT05696626) is an open-label, phase 3, multicenter study evaluating the efficacy, safety, and tolerability of LAS plus Abema versus fulv plus Abema. Key inclusion criteria are pre- and postmenopausal women and men aged ≥18 yrs; ER+/HER2-, locally advanced and/or mBC (measurable and/or non-measurable disease); ≥1 acquired ESR1 mutation; progression on an aromatase inhibitor plus palbociclib or ribociclib as their first hormonal treatment for advanced/mBC; and ≤1 line of chemotherapy in the advanced/metastatic setting. Patients will be randomized 1:1 to receive LAS 5 mg/day plus Abema 150 mg BID, or fulv 500 mg IM on days 1, 15, and 29, then once monthly plus Abema 150 mg BID. Treatment will continue until progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint is PFS; key secondary endpoints are ORR, overall survival, CBR, duration of response, and time to response. Time to cytotoxic chemotherapy, quality of life, and safety will also be evaluated. Blood samples for circulating tumor DNA (ctDNA) will be collected for genomic analyses at screening, at weeks 4 and 8 and every 8 weeks thereafter, and at the final visit. Outcomes with LAS/Abema and fulv/Abema will be compared using a stratified Cox proportional hazards model and stratified logrank test. Expected PFS is ≥10.3 mos for LAS/Abema and 7 mos for fulv/Abema (PFS hazard ratio of 0.68 at final analysis). The target sample size is 400, to achieve 90% power with a one-sided type I error rate of 0.025 after 285 PFS events. Full recruitment is expected to occur over 18 mos at approximately 125 global sites. 1. Goetz MP, et al. Ann Oncol. 2023;34:1141-1151. 2. Damodaran S, et al. Ann Oncol. 2023;34:1131-1140. Clinical trial information: NCT05696626 .

PURPOSE BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib. METHODS Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived. RESULTS Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months). CONCLUSION This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

Abstract Introduction: Acquired ESR1 mutations (mutESR1) after long-term endocrine therapy drive treatment resistance, metastasis, and poor prognosis for patients (pts) with ER+/HER2- metastatic breast cancer (mBC). Lasofoxifene (LAS), a selective estrogen receptor modulator, alone or with a CDK4/6 inhibitor (CDK4/6i) reduced tumor growth better than fulvestrant (Fulv) in mutESR1 BC xenograft models. ELAINE 1 is a randomized trial of LAS vs Fulv in pts with mutESR1 and prior progression on aromatase inhibitor and CDK4/6i. Preliminary results (ESMO 2022) showed that LAS prolonged median progression-free survival (mPFS) compared with Fulv with a favorable safety profile. Here, we report changes in ESR1 ctDNA mutant allele frequency (MAF) from baseline to 8 wks and their associations with clinical benefit (CB) and mPFS. Methods: ELAINE 1 pts were randomized to oral LAS 5 mg daily or IM Fulv 500 mg on days 1, 15, and 29, then every 4 wks, until disease progression or severe toxicity. ctDNA mutESR1 mutations (baseline and 8 wks) were assessed using the Sysmex Inostics OncoBeam or SafeSeq assays—which detect mutESR1 at low allele fractions. MAF changes from baseline to wk 8 were characterized as decreased (decrease in ESR1 MAF or fully cleared), increased (increase in MAF), or equivocal (polyclonal patients [>1 mutESR1] with some increasing and decreasing MAF trends); correlations with PFS and CB were explored. Efficacy measures included objective response rate (ORR), PFS, and CB at 24 wks (CB defined as response or stable disease ≥24 wks). Results: 103 pts received LAS (n=52) or Fulv (n=51). Most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal. Of the 61 pts with evaluable baseline and wk 8 ctDNA, LAS decreased mutESR1 MAF in 29/35 pts (83% [11 complete clearance]) while Fulv decreased mutESR1 MAF in 16/26 pts (61.5% [6 complete clearance]) (Table). mPFS with LAS was 8 and 4 mos for pts with decreased/cleared MAF and increased MAF, respectively, and with Fulv was 4.5 and 2.8 mos, respectively (Table). LAS decreased the common mutESR1 variants more frequently than Fulv (median relative change -87.1% vs -14.7%). In pts with decreased MAF, CB was observed in 16/29 LAS pts (55%) and 4/16 Fulv pts (25%). The predictiveness of ESR1 MAF clearance for CB was also explored. Of 11 pts with ESR1 MAF clearance taking LAS, 10 achieved CB, yielding a positive predictive value (PPV) of 90.9%. In contrast, 2/6 pts with ESR1 MAF clearance taking Fulv had CB for a PPV of 33.3%. Sensitivity for predicting CB based on direction of ESR1 MAF change was 94% with LAS and 80% with Fulv. In pts with Y537S MAF (n=33), LAS decreased Y537S in 13/15 (87%), with a median relative MAF decrease of 89%. In marked contrast, Fulv increased Y537S MAF in 11/18 pts (61%), corresponding to an MAF relative increase of 82%. LAS and Fulv resulted in complete clearance of Y537S MAF in 33% and 6% of pts, respectively. Conclusion: Our data demonstrate that LAS more effectively decreased or cleared mutESR1 than Fulv. Further, mutESR1 clearance was associated with prolonged PFS and more CB in LAS but not Fulv pts, suggesting that LAS results in robust mutESR1 target engagement. Taken together, our data suggest mutESR1 as a potential liquid biomarker for predicting response to LAS in mutESR1, endocrine-resistant mBC pts. Table. Change from baseline to week 8 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; PFS, progression-free survival. Citation Format: Matthew P. Goetz, Einav Gal-Yam, Daniel Stover, Sarah L. Sammons, Stephanie L. Graff, Grace Wang, Massimo Cristofanilli, Gary Riordan, Hillary S. Sloane, Dominic Carroll, Paul V. Plourde, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-04.