Rapid Fire 7

H. Rugo¹, S. M. Tolaney², N. Chan³, G. Borges⁴, R. Yerushalmi⁵, M. Sharifi⁶, W. McHayleh⁷, T. Beck⁸, N. Vidula⁹, E. Hamilton¹⁰, K. J. Rinn¹¹, J. O’Shaughnessy¹², G. Curigliano¹³, J. Cortés¹⁴, P. Romero¹⁵, G. Tonini¹⁵, A. Paoli¹⁶, M. Binaschi¹⁶, L. Cheng¹⁷, J. Crozier¹⁷, T. Wasserman¹⁸, V. Kaklamani¹⁹; ¹Breast Medical Oncology, City of Hope Duarte Cancer Center, Duarte, CA, ²Breast Oncology, Dana-Farber Cancer Institute, Boston, MA, ³Breast Medical Oncology, NYU Langone Health, New York, NY, ⁴Breast Medical Oncology, Catarina Pesquisa Clínica, Santa Catarina, BRAZIL, ⁵Breast Medical Oncology, Rabin Medical Center, Petah Tikva, ISRAEL, ⁶Breast Medical Oncology, University of Wisconsin, Madison, WI, ⁷Breast Medical Oncology, Adventhealth Cancer Institute, Orlando, FL, ⁸Breast Medical Oncology, Highlands Oncology, Springdale, AR, ⁹Breast Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ¹⁰Breast Medical Oncology, Sarah Cannon Research Institute, Nashville, TN, ¹¹Breast Medical Oncology, Cancer Care Northwest, Spokane, WA, ¹²Breast Medical Oncology, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, ¹³Breast Medical Oncology, Istituto Europeo di Oncologia, IRCCS, and University of Milano, Milano, ITALY, ¹⁴Breast Medical Oncology, International Breast Cancer Center (IBCC), Quironsalud Group, Barcelona, SPAIN, ¹⁵Biostatistics, Menarini Group, Florence, ITALY, ¹⁶Clinical Development, Menarini Group, Florence, ITALY, ¹⁷Clinical Development, Menarini Group, New York, NY, ¹⁸Medical Affairs, Menarini Group, New York, NY, ¹⁹Breast Medical Oncology, University of Texas Health Sciences Center, San Antonio, TX.

Background: Disease progression in patients (pts) with ER+/HER2- mBC on 1L endocrine therapy (ET) + CDK4/6i is associated with mechanisms of resistance that impact the efficacy of subsequent therapy. Later treatment options include ET ± targeted agents (CDK4/6i or PI3K/AKT/mTOR pathway inhibitors). Clinical trials have shown mPFS of 3.6-6.8 mo with ET + everolimus(Cook 2021, Vasseur 2024) and mPFS of 5.3-9.4 mo by switching the CDK4/6i(Kalinsky 2023, 2024, Jhaveri 2024). Elacestrant (Ela) significantly improved PFS vs SOC ET (ESR1m tumors HR 0.55; 95% CI0.39-0.77; all pts HR 0.70; 95% CI 0.55-0.88) with manageable safety in the EMERALD trial (Bidard 2022). Based on encouraging clinical activity and tolerability from Ph 1b, we evaluated the Ph 2 combinations of Ela + everolimus(Eve) or abemaciclib (Abema) in all pts and clinically relevant subgroups. Methods: ELEVATE is evaluating elacestrant combined with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib,or palbociclib to address different resistance mechanisms. Patients with ER+/HER2- mBC and 1-2L of prior ET are eligible regardless of ESR1mstatus. Prior CDK4/6i is required for Arm B (Ela + Eve) and Arm C (Eve + Abema). Patients with no prior CDK4/6i were enrolled in Arm D (Ela + Abema). The Ph 2objective is to evaluate PFS with each combination. ESR1 and PIK3CA mutation status were evaluated in pts for both combinations Ela + Eve (n=48) and Ela + Abema(n=50). Results: As of September 2025,50 pts enrolled in Arm B (Ela + Eve), and 60 enrolled in Arms C and D (Ela + Abema combinations, n=30 each). Baseline characteristics include pts with visceral metastases (72% Arm B, 92% Arms C/D), primary ET resistance (20% Arm B, 15%Arms C/D), ESR1m (42% Arm B, 33% Arms C/D), and PIK3CAm (50% Arm B,27% Arms C/D). PFS benefit was consistent across subgroups, including those with visceral metastases, prior fulvestrant or primary ET resistance. The Ela combinations demonstrate safety consistent with the known safety profiles of Eve or Abema + SOC ET. Ph 2 Ela + Eve ORR was 19.5%,SD was 63.4%, DCR 82.9%, and mDOR 8.54 months. Ph 2 Ela + Abema ORR was 24.6%,SD was 66.7%, DCR 91.2%, and mDOR 14.75 months. mPFS results are summarized in Table 1. The median follow period for Ela + Abema is 8.6 (6.5-11.1) months. Updated efficacy results with longer follow-up will be provided for this combination. Conclusion: Elacestrant in combination shows a consistent PFS benefit irrespective of ESR1m status in pts with ER+/HER2-mBC after progressive disease on ET ± prior CDK4/6i. Elacestrant has the potential to become an ET backbone for combination strategies with targeted agents, supporting an all-oral approach that may delay the need for chemo or ADC-based regimens in this patient population. Table 1:Phase 2 mPFS, mo[95% CI] in all patients and subgroups

NR, not reached

M. De Laurentiis¹, A. M. Ferreira², J. Gligorov³, E. Dobi⁴, L. Costa⁵, M. Vidal⁶, A. S. Knop⁷, T. Bachelot⁸, E. Senkus⁹, M. Colleoni¹⁰, P. Schmid¹¹, A. Santoro¹², G. Zhbantov¹³, J. Foglietta¹⁴, M. Miller¹⁵, P. Serra¹⁶, A. Heniquez¹⁵, P. Chaudhary¹⁷, R. Haidinger¹⁸, S. Kuemmel¹⁹; ¹Department of Breast and Thoracic Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy, ²Portuguese Oncology Institute of Porto, Porto, Portugal, ³Institut Universitaire de Cancérologie AP-HP, Sorbonne Université, Paris, France, ⁴CHU Besancon Jean Minjoz, Besancon, France, ⁵Hospital de Santa Maria, Serviço de Oncologia Médica, Avenida Professor Egas Moniz 1649-035 Lisboa, Lisoba, Portugal, ⁶Hospital Clinic i Provincial de Barcelona, Barcelona, Spain, ⁷DBCG, Rigshospitalet – Blegdamsvej 9, 2100, København, Denmark, ⁸CLCC Centre Leon Berard, Lyon, France, ⁹Medical University of Gdańsk, Gdańsk, Poland, ¹⁰IEO, Istituto Europeo Di Oncologia IRCCS, Milano, Italy, ¹¹Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom, ¹²IRCCS Ist Clinico Humanitas, Milan, Italy, ¹³Medical Center Nadezhda Clinical, Sofia, Bulgaria, Sofia, Bulgaria, ¹⁴S.C. Oncologia Medica e Traslazionale; Az.Ospedaliera Santa Maria di Terni, Terni, Italy, ¹⁵Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, NJ, ¹⁶Oncology Global Development, Novartis Pharma AG, Basel, Switzerland, ¹⁷Novartis Healthcare Private Limited, Hyderabad, India, ¹⁸Brustkrebs Deutschland e.V. (German Breast Cancer Association), Hohenbrunn I, Germany, ¹⁹Breast Unit, Kliniken Essen-Mitte, Essen, Germany, Charité – Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany

Background: Alpelisib (ALP), an α-specific PI3K inhibitor, plus fulvestrant (FUL) improved disease control with a manageable safety in patients (pts) with HR+, HER2− advanced breast cancer (ABC) harboring a PIK3CA-m in SOLAR-1 and in BYLieve Cohort A trials. We report primary results from the EPIK-B5 study, comparing ALP+FUL vs placebo (PBO)+FUL in men/postmenopausal women with PIK3CA-m HR+, HER2− ABC who had progressed on cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)+aromatase inhibitor (AI). Methods: EPIK-B5 was a phase 3, double-blind, PBO-controlled study. Pts (n=188) were randomised 1:1 to ALP+FUL (arm 1) or PBO+FUL (arm 2). The primary endpoint was progression-free survival (PFS) by Blinded Independent Review Committee [BIRC]. Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), time to response (TTR), PFS by PIK3CA-m in baseline ctDNA, adverse events (AEs), time to definitive deterioration of Eastern Cooperative Oncology Group (ECOG) performance status, change in global health status and symptom scale scores of the EORTC QLQ-C30, and time to progression on next line treatment or death (PFS2) by investigator assessment. Results: Baseline characteristics are shown in the Table. At primary analysis (data cutoff Oct 2024), median follow-up duration was 17.7 (1.4-33.1) months (mo). The median PFS (BIRC) was 7.4 and 2.8 mo in arm 1 and 2, respectively, (HR: 0.52, 95% CI: 0.37,0.72, log-rank p<0.0001). Median OS was not reached for arm 1 and was 22.6 mo for arm 2 (HR:0.60, 95% CI: 0.36,1.01). In pts with measurable disease, (n= 85 vs 90 in arm 1 vs 2) ORR was 24.7% vs 4.4% and CBR was 47.1% vs 22.2% in arm 1 vs 2, respectively. Dose reductions (45.7% vs 0%) and interruptions (68.5 vs 13.8%) were more frequent for ALP+FUL. Most common AEs (all grades; ≥30%) in arm 1 and 2 were hyperglycemia (72.8% vs 11.7%), diarrhea (51.1% vs 11.7%), nausea (44.6% vs 13.8%), decreased appetite and rash (30.4% each in both arms). Discontinuations in arm 1 and 2 due to AEs (all grades) were 27.2% vs 2.1% respectively. On-treatment deaths were comparable (5.4% vs. 6.4%). At the pre-planned final PFS analysis (cut-off May 2025; median duration 23.5 mo), the median OS was 29.5 and 23.8 months in arms 1 and 2, respectively (HR:0.64, 95% CI: 0.41-0.99, p=0.021). Conclusion: EPIK-B5 met its primary objective with ALP+FUL showing a statistically significant and clinically meaningful improvement in PFS in patients with HR+, HER2− ABC harboring a PIK3CA-m after CDK4/6i. There was a positive trend for a prolonged OS in favor of ALP+FUL over PBO with about 5.7 mo improvement in the median OS. There were no new safety signals.

F. Bidard¹, E. L. Mayer², Y. Park³, W. Janni⁴, C. Ma⁵, M. Cristofanilli⁶, G. Bianchini⁷, K. Kalinsky⁸, H. Iwata⁹, S. Chia¹⁰, A. Brufsky¹¹, P. Fasching¹², Z. Nowecki¹³, J. Pascual¹⁴, E. Gal-Yam¹⁵, W. Chung¹⁶, S. Im¹⁷, A. Zambelli¹⁸, F. Dalenc¹⁹, M. Oliveira²⁰, S. Fox²¹, M. Selvi Miralles²¹, C. Morrow²², C. Huang Bartlett²³, N. C. Turner²⁴; ¹Institut Curie, Paris, FRANCE, ²Dana-Farber Cancer Institute, Boston, MA, ³Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ⁴Universitätsklinikum Ulm, Ulm, GERMANY, ⁵Washington University School of Medicine, Saint Louis, MO, ⁶Weill-Cornell Medicine / New York-Presbyterian Hospital, New York, NY, ⁷IRCCS Ospedale San Raffaele, Milan, ITALY, ⁸Winship Cancer Institute, Atlanta, GA, ⁹Nagoya City University, Nagoya, JAPAN, ¹⁰BC Cancer Agency, Vancouver, BC, CANADA, ¹¹UMPC Magee-Womens Hospital, Pittsburgh, PA, ¹²University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, GERMANY, ¹³Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie, Warsaw, POLAND, ¹⁴Medical Oncology Department, Hospital Universitario Virgen de la Victoria. IBIMA, Málaga, SPAIN, ¹⁵Sheba Medical Center, Tel-Hashomer, ISRAEL, ¹⁶National Cheng-Kung University Hospital, Tainan, TAIWAN, ¹⁷Cancer Research Institute, Seoul National University College of Medicine, Seoul, KOREA, REPUBLIC OF, ¹⁸IRCCS Istituto Clinico Humanitas, Milan, ITALY, ¹⁹Institut Claudius Regaud, IUCT-Oncopole, Toulouse, FRANCE, ²⁰Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, SPAIN, ²¹Late Development, Oncology R&D, AstraZeneca, Cambridge, UNITED KINGDOM, ²²Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UNITED KINGDOM, ²³Late Development, Oncology R&D, AstraZeneca, Gaithersburg, MD, ²⁴Royal Marsden Hospital, London, UNITED KINGDOM.

Background At SERENA-6 interim analysis, switching to CAMI, with continued CDK4/6i, at ESR1m emergence during 1L aromatase inhibitor (AI) + CDK4/6i significantly improved PFS, extending time on first-line therapy, and delayed time to deterioration (TTD) in global health status and quality of life (GHS/QOL) (DCO: Nov 28, 2024). We report the prespecified final PFS analysis and an exploratory analysis of ESR1m ctDNA dynamics. Methods SERENA-6, a randomized, double-blind, phase 3 trial, enrolled pts with HR+/HER2- ABC who had received ≥6 months of 1L AI (anastrozole/letrozole) + CDK4/6i (palbociclib/ribociclib/abemaciclib). Pts had ctDNA tested for ESR1m every 2-3 months, coinciding with routine clinical assessments. At ESR1m detection, pts without evidence of disease progression were randomized 1:1 to switch to CAMI (75 mg) with continued CDK4/6i (type and dose) + placebo for AI vs continuing AI + CDK4/6i + placebo for CAMI. The primary endpoint was PFS (per RECIST v1.1). Key secondary endpoints were PFS2 and OS. Chemotherapy-free survival was a secondary endpoint; TTD in GHS/QOL was an exploratory endpoint. ctDNA was analyzed by next-generation sequencing of plasma samples at baseline and Cycle 3 Day 1 (C3D1). This final PFS analysis was planned after ~195 PFS events. DCO2: June 30, 2025. Results 315 pts were randomized to switch to CAMI (n=157) or continue AI (n=158) with continued CDK4/6i. At DCO, median follow-up was 18.7 months. Updated results are shown in the Table and were consistent with primary analyses. PFS benefit was consistent across pt subgroups. At C3D1 (8 weeks) ESR1m allele frequency (AF) was profoundly reduced in the CAMI + CDK4/6i arm (median change from baseline, −100% [IQR: −100 to −100]) and increased in the AI + CDK4/6i arm (median change from baseline, +66.7% [IQR: −67.9 to +465.0], Wilcoxon P<0.00001). In the AI + CDK4/6i arm, ESR1m AF increased >500% from baseline in 24.4% pts vs 0.8% in the CAMI + CDK4/6i arm. OS results remained immature (22%). Updated safety data were consistent with previous results. Rates of treatment discontinuation due to AEs were 1.3% for CAMI and 2.6% for AI. Conclusions Consistent with the primary results, CAMI + CDK4/6i significantly prolongs PFS in pts with HR+/HER2- ABC and ESR1m emergence during 1L AI + CDK4/6i and ahead of disease progression. CAMI + CDK4/6i profoundly reduced ESR1m AF within 8 weeks, whereas it increased for many pts continuing AI + CDK4/6i. PFS2 and chemotherapy or antibody drug-conjugate-free survival hazard ratios favor the CAMI + CDK4/6i arm. No new safety signals were observed. These results further support an early switch to CAMI + CDK4/6i during 1L therapy to delay disease progression.

B. Pistilli¹, R. Layman², G. Curigliano³, F. André¹, M. Cristofanilli⁴, M. Martín⁵, R. Wesolowski⁶, S.-B. Kim⁷, G. Kim⁸, M. Richardet⁹, J. Nadal¹⁰, A. Ring¹¹, J. Martinez Rodriguez¹², H. Han¹³, A. Giordano¹⁴, K. Moss¹⁵, S. Mutka¹⁵, B. Sullivan¹⁵, S. Suzuki¹⁵, I. Gorbatchevsky¹⁵, S. Hurvitz¹⁶; ¹Gustave Roussy, Villejuif, France, ²The University of Texas MD Anderson Cancer Center, Houston, TX, ³Istituto Europeo di Oncologia, IRCCS; University of Milano, Milano, Italy, ⁴Weill Cornell Medical College, New York, NY, ⁵Hospital Gregorio Marañón, Universidad Complutense, GEICAM, CIBERONC, Madrid, Spain, ⁶The Ohio State University Comprehensive Cancer Center, Columbus, OH, ⁷Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of, ⁸Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of, ⁹Sanatorio Aconcagua, Córdoba, Argentina, ¹⁰Alexander Fleming Institute, Buenos Aires, Argentina, ¹¹The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom, ¹²Filios Alta Medicina SA de CV, Nuevo Leon, Mexico, ¹³Moffitt Cancer Center, Tampa, FL, ¹⁴Dana-Farber Cancer Institute, Boston, MA, ¹⁵Celcuity, Minneapolis, MN, ¹⁶Fred Hutchinson Cancer Center; University of Washington, Seattle, WA

***This abstract is an updated version of the previously submitted shell abstract (#286), which was accepted for a rapid-fire oral presentation (RF4-03). Background: Second-line treatment for HR+/HER2- ABC after endocrine therapy (ET) + a CDK4/6 inhibitor (CDK4/6i) is associated with a poor clinical outcome. Treatment resistance likely involves the PAM pathway; therefore, adding a PAM inhibitor (PAMi) to ET + CDK4/6i after progression on CDK4/6i may restore sensitivity and prevent adaptive PAM pathway activation. Gedatolisib is a highly potent multitarget inhibitor of all Class I PI3K isoforms plus mTORC1 and mTORC2 that provides comprehensive PAM blockade. In preclinical studies, gedatolisib demonstrated superior potency and cytotoxicity compared to alpelisib, capivasertib, and everolimus, regardless of PI3K-pathway mutation status, and combinations of gedatolisib + fulvestrant, with and without palbociclib, were active in treatment-naive and resistant cell lines. The phase 3 VIKTORIA-1 trial was designed to evaluate the safety and efficacy of gedatolisib-based therapy in patients with HR+/HER2- ABC that progressed during or following CDK4/6i and aromatase inhibitor therapy. Based on the PIK3CA screening result, patients are enrolled to Study 1 (PIK3CA-WT) or Study 2 (PIK3CA-mutated disease). Herein, we report updated results from Study 1. Methods: VIKTORIA-1 is a randomized, open-label, phase 3 trial. Eligible patients must have HR+/HER2- ABC, disease progression during or after a CDK4/6i + nonsteroidal aromatase inhibitor, no chemotherapy for ABC, no prior PAMi, and radiologically evaluable disease (per RECIST v1.1). Study 1 patients (PIK3CA WT) were randomized 1:1:1 to: gedatolisib + palbociclib + fulvestrant (triplet), gedatolisib + fulvestrant (doublet), or fulvestrant, stratified by presence of visceral metastasis, time to radiological disease progression on immediate prior therapy, and geographic region. Treatment was administered in 28-day cycles as follows: gedatolisib 180 mg IV weekly for 3 weeks on/1 week off; palbociclib 125 mg po daily for 21 days; fulvestrant 500 mg IM every 2 weeks (cycle 1) then every 4 weeks. Co-primary endpoints were progression-free survival (PFS) assessed by blinded independent central review comparing the triplet to fulvestrant, then, if positive, the doublet to fulvestrant. Statistical comparisons were performed by stratified log-rank test. Additional endpoints include overall survival, response, safety, and quality of life (QOL). Results: At data cut-off (May 30,2025), 392 patients with PIK3CA WT disease had been randomized, and median study follow-up was 10.1 mos. The trial met its primary endpoints, with median PFS for the triplet vs fulvestrant of 9.3 vs. 2.0 months (HR, 0.24; 95% CI, 0.17-0.35; p<0.0001) and doublet (7.4 vs. 2.0 months; HR, 0.33; 95% CI, 0.24-0.48; p<0.0001), with PFS benefit maintained across pre-specified subgroups (ESMO 2025). Safety profiles were generally consistent with the individual agents, with low rates of discontinuation of assigned therapy due to treatment-related adverse events (2.3% for triplet; 3.1% for doublet). Hyperglycemia incidence was 9.2% and 11.5%, respectively, with grade 3 severity in 2.3% of pts in both gedatolisib groups, and no grade 4 events. For this update, additional sub-group efficacy analyses, QOL outcomes, and expanded safety data will be presented. Conclusion: These updated results support gedatolisib combination therapy as a potential new standard of care for the 2L treatment of patients with HR+/HER2-/PIK3CA WT ABC.

N. C. Turner¹, M. Oliveira², S. J. Howell³, F. Dalenc⁴, W.-P. Chung⁵, J. Cortés⁶, H. L. Gomez Moreno⁷, X. Hu⁸, K. Jhaveri⁹, P. Krivorotko¹⁰, G. Lerzo¹¹, S. Loibl¹², S. Morales Murillo¹³, Z. Nowecki¹⁴, M. Okera¹⁵, Y. Park¹⁶, J. Sohn¹⁷, M. Toi¹⁸, L. Zhukova¹⁹, E. DeBruin²⁰, A. Nardone²¹, A. Spencer²⁰, M. Fulford²², G. Schiavon²⁰, H. S. Rugo²³; ¹Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom, ²Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain Breast Cancer Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, ³The Christie NHS Foundation Trust, Manchester, United Kingdom, ⁴Institut Claudius Regaud, Institut Universitaire du Cancer – Oncopole, Toulouse, France, ⁵Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng, Tainan, Taiwan, ⁶IBCC, Quiron Group, Barcelona, SPAIN; IOB Madrid, Hospital Beata María Ana, Madrid, SPAIN; Hospital Universitario Torrejón, Madrid, SPAIN; Universidad Europea de Madrid, Madrid, SPAIN; MEDSIR, Ridgewood (New Jersey, USA), Barcelona (SPAIN), Madrid, Spain, ⁷Instituto Nacional de Enfermedades Neoplásicas (INEN), Departamento de Oncología Médica, Lima, Peru Universidad Ricardo Palma, Lima, Peru, ⁸Shanghai Cancer Center, Fudan University, Shanghai, China, ⁹Memorial Sloan Kettering Cancer Center, New York, New York, USA; Weill Cornell Medical College, New York, NY, ¹⁰Petrov Research Institute of Oncology, Peterburg, Russian Federation, ¹¹CENIT Centro Medico de Neuro, Investigacion y Tratamiento, Buenos Aires, Argentina, ¹²GBG Forschungs GmbH, Neu-Isenburg, Germany Goethe University, Frankfurt, Germany, ¹³Institut de Recerca Biomèdica, Barcelona, Spain, ¹⁴The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland, ¹⁵ICON Cancer Centre, Adelaide, Australia, ¹⁶Samsung Medical Center, Sungkunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea, Republic of, ¹⁷Yonsei University College of Medicine – Yonsei Cancer Center, Seoul, Korea, Republic of, ¹⁸Affiliation at the time the work was conducted: Kyoto University Hospital, Kyoto, Japan, ¹⁹Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation, ²⁰Oncology R&D, AstraZeneca, Cambridge, United Kingdom, ²¹Oncology R&D, AstraZeneca, Barcelona, Spain, ²²Oncology R&D, AstraZeneca, Warsaw, Poland, ²³Affiliation at the time the work was conducted: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

Background: Based on the results of the global Phase 3 CAPItello-291 trial, the pan-AKT inhibitor capivasertib (C) is recommended in combination with fulvestrant (F) for patients (pts) with PIK3CA/AKT1/PTEN-altered HR+ ABC progressing after ≥1 line of endocrine therapy-based treatment. The primary analysis showed clinically meaningful improvement in progression-free survival (PFS) in both overall and PIK3CA/AKT1/PTEN-altered populations (identified based on tumor sequencing) treated with C + F vs placebo (pbo) + F. Here, we report exploratory ctDNA analyses. Methods: Eligible pts with HR+/HER2- ABC had progression ≤12 months of (neo)adjuvant aromatase inhibitor (AI) treatment, or while on prior AI-based treatment for ABC. Pts were randomized 1:1 to C + F or pbo + F. PIK3CA/AKT1/PTEN alteration status was determined in tumor tissue collected at study entry assessed by FoundationOne^®CDx NGS, and in baseline blood samples for ctDNA analysis using Guardant Infinity^TM which also reports methylation-based ctDNA tumor fraction (TF). Results: Of 708 pts in the overall population, 658 (92.9%) had a ctDNA sample for analysis. Overall concordance between ctDNA and tissue was 83.3% (Table). No/low shedding (TF<0.1%) was found in 49% of ctDNA samples from pts with alterations detected in tissue but not ctDNA (n=63), compared with 1% of ctDNA samples from pts with alterations detected in both tissue and ctDNA (n=207). Alterations were detected by ctDNA alone in 72/700 pts (10.3%). Of these, 42 had no tissue result; the remaining 30 alterations detected in ctDNA but not tissue were enriched for PTEN: 18 pt samples had ≥1 PTEN alteration, most large genomic rearrangements. In the 279/658 (42%) pts with detected ctDNA alterations, baseline characteristics were generally well-balanced between treatment arms: median (range) age was 58 (29-86) years, 80.3% were postmenopausal, 77.4% had prior CDK4/6i and 19.4% prior chemotherapy for ABC, 53.4% had co-occurring ESR1m. ECOG PS was worse in the C + F (PS 1: 38.0%) vs pbo + F (PS 1: 26.3%) arm. In the ctDNA-altered subgroup, PFS hazard ratio with C + F vs pbo + F was 0.43 (95% CI 0.33-0.56); co-occurring ESR1m detected 0.52 (0.36-0.76); ESR1m not detected 0.36 (0.23-0.54). In pts with an alteration detected in either tissue or ctDNA (n=359), PFS hazard ratio was 0.49 (0.38-0.62), in pts non-altered by ≥1 method (n=335) was 0.74 (0.58-0.95). Conclusions: ctDNA analysis offers a minimally invasive option to identify PIK3CA/AKT1/PTEN alterations in HR+ ABC, particularly for pts without suitable tumor tissue analysis. However, ctDNA testing alone may miss alterations, such as in cases of low ctDNA shedding (TF <0.1%), warranting a confirmatory tissue test. The PFS benefit of C + F vs pbo + F in the ctDNA-altered group was consistent with the primary tissue-based analysis. Clinical benefit with C + F was observed irrespective of ESR1m.

V. Dieras¹, F. C. Bidard², L. Roca³, J. Pierga², T. Bachelot⁴, I. Desmoulins⁵, C. Jouannaud⁶, X. Durando⁷, C. Delbado⁸, S. Lavau-Denes⁹, F. Minne¹⁰, A. C. Hardy-Bessard¹¹, K. Bourcier¹², O. Derbel¹³, J. Grenier¹⁴, F. Clatot¹⁵, S. Renault¹⁶, J. Lemonnier¹⁷, C. Vissac-Sabatier¹⁷, J. Péron¹⁸, G. Freyer¹⁹; ¹Centre Eugène Marquis, Rennes, FRANCE, ²Institut Curie, Paris, FRANCE, ³Institut de Cancérologie de Montpellier, Montpellier, FRANCE, ⁴Centre Léon Bérard, Lyon, FRANCE, ⁵Centre Georges François Leclerc, Dijon, FRANCE, ⁶Institut Jean Godinot, Reims, FRANCE, ⁷Centre Jean Perrin, Clermont-Ferrand, FRANCE, ⁸Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, FRANCE, ⁹Chu de Limoges, Limoges, FRANCE, ¹⁰Centre Hospitalier de la Côte Basque, Bayonne, FRANCE, ¹¹Hôpital Privé des Côtes d’Armor, Plérin, FRANCE, ¹²Centre Hospitalier de Pau, Pau, FRANCE, ¹³Hôpital Privé Jean Mermoz, Lyon, FRANCE, ¹⁴Institut Sainte Catherine, Avignon, FRANCE, ¹⁵Centre Henri Becquerel, Rouen, FRANCE, ¹⁶Institut Curie – Laboratory Circulating Tumor biomarkers, Paris, FRANCE, ¹⁷Unicancer, Paris, FRANCE, ¹⁸Hospices Civils de Lyon – Centre Hospitalier Lyon Sud, Oullins-Pierre-Bénite, FRANCE, ¹⁹CHU Saint-Etienne, Saint-Priest-en-Jarez, FRANCE.

Background: Patients with HR+/HER2- ABC and visceral crisis were excluded from CDK4/6 inhibitor pivotal trials in fist line, and CT remains an option in these patients. Methods: The AMBRE trial (NCT04158362) assessed the efficacy of abemaciclib + ET compared to CT in pts with high visceral tumor burden. Eligible patients had HR+/HER2– ABC, ECOG 0–2, measurable disease, no prior systemic therapy for ABC, and high visceral burden (≥2 visceral sites, ≥3 lesions in one organ, or visceral disease with LDH > ULN). Pts were randomized 1:1 to abemaciclib 150 mg BID + ET (letrozole or fulvestrant (based ET sensitivity) ± OFS) or CT at investigator’s choice: weekly paclitaxel (80 mg/m²) or capecitabine (2000–2500 mg/m²/day, d1–14 q21d).The primary endpoint was PFS; 118 events provided 80% power to detect an increase in median PFS from 8 to 13 months (HR=0.6, α=0.05). Secondary endpoints included PFS2, OS, ORR, DoR, safety, and QoL. Circulating Tumors Cells (CTC) count was performed (CellSearch®) at baseline, at Day 21(D1C2) and at progression. Results 180 patients were enrolled (abemaciclib: n=91; CT: n=89; 33.7% paclitaxel, 66.3% capecitabine) from 06.2020 to 07.2024. Median follow-up was ~26 months. Baseline characteristics were balanced: median age 62.5 years, 77.2% with liver metastases, 38% were ET resistant, 62% ET sensitive, including 27% with de-novo metastatic disease. Median PFS was 13.9 months in abemaciclib arm versus 7.0 months in CT arm (HR=0.67, 95% CI 0.46 to 0.98, p=0.035). The PFS curves diverged as early at 4 months. DoR was significantly longer with abemaciclib (HR=0.46, p=0.023). No statistically significant difference was observed in ORR, QoL, PFS2 and OS. No new safety signal was observed. At baseline, the median number of CTCs was 5 (range 0-556). The prognostic value of CTC count was confirmed and CTC count changes under treatment showed similar patterns across study arms. Other translational research with ctDNA (ESR1 and PIK3CA) are ongoing in order to better characterize this population with high burden disease and their impact according to treatment arm. Conclusions: AMBRE demonstrates that Abemaciclib + ET significantly improves PFS over CT in first-line treatment of HR+/HER2– ABC with high visceral tumor burden and high CTC count, supporting its use as a standard option in this setting. Clinical trial identification NCT04158362 Legal entity responsible for the study UNICANCER UCBG Financial support: Lilly

A. DeMichele¹, A. Dueck², M. Gnant³, D. Hlauschek⁴, M. Martin⁵, A. Wolff⁶, G. Rubovsky⁷, F. Henao⁸, O. Hahn⁹, A. Chan¹⁰, A. Brusky¹¹, P. Morris¹², H. Burstein¹³, G. Huber¹⁴, D. Anderson¹⁵, L. Garcia-Estevez¹⁶, G. Pfeiler³, H. Rugo¹⁷, N. Zdenkowski¹⁸, S. Gampenrieder¹⁹, N. Wolmark²⁰, D. Sabanathan²¹, K. Miller²², D. Cameron²³, E. Winer²⁴, C. Brunner²⁵, E. Gauthier²⁶, P. O’Brien²⁷, C. Fesl⁴, E. Mayer¹³; ¹University of Pennsylvania, Philadelphia, PA, ²Mayo Clinic, Phoenix, AZ, ³Medical University of Vienna, Vienna, Austria, ⁴ABCSG, Vienna, Austria, ⁵Hospital General Universitario Gregorio Marañon, Madrid, Spain, ⁶John Hopkins University, Baltimore, MD, ⁷National Institute of Oncology, Budapest, Hungary, ⁸Hospital Universitario Virgen Macarena, Sevilla, Spain, ⁹University of Chicago Comprehensive Cancer Center, Chicago, IL, ¹⁰Breast Cancer Research Centre, Perth, Australia, ¹¹University of Pittsburgh, Pittsburgh, PA, ¹²Beaumont Hospital, Dublin, Ireland, ¹³Dana-Farber Cancer Institute, Boston, MA, ¹⁴Ordination Dr Huber, Kärnten, Austria, ¹⁵Metro Minnesota Community Oncology Research Consortium, St. Louis Park, MN, ¹⁶MD Anderson Cancer Center, Madrid, Spain, ¹⁷University of San Francisco, San Francisco, CA, ¹⁸Calvary Mater Newcastle, New South Wales, Australia, ¹⁹Salzburg Cancer Research Institute, Salzburg, Austria, ²⁰NSABP Foundation, Pittsburgh, PA, ²¹Macquarie University Hospital, Sydney, Australia, ²²Indiana University, Indianapolis,, IN, ²³Cancer Research UK Edinburgh Centre, Edinburgh, United Kingdom, ²⁴Yale University, New Haven, CT, ²⁵Medical University Innsbruck, Innsbruck, Austria, ²⁶Pfizer Inc., San Francisco, CA, ²⁷Mayo Clinic, Rochester, MN

PURPOSE: CDK4/6 inhibitors (CDK4/6i), used in combination with endocrine therapy (ET), are standard of care for advanced and higher risk early stage hormone receptor-positive (HR+), HER2 negative (HER2-) breast cancer. PALLAS investigated the addition of 2 years (y) of palbociclib to adjuvant ET (ET/P) compared to ET alone in patients (pts) with stage II-III HR+/HER2- breast cancer. We now present overall survival (OS) with 7-y outcomes and impact of post-recurrence therapy.PATIENTS AND METHODS: This global phase III trial randomized pts to ET for at least 5 y with or without 2 y of P. Primary endpoint was iDFS; distant recurrence-free survival (DRFS) and OS were preplanned endpoints. Kaplan Meier estimates and hazard ratios (HR) from Cox and Fine & Gray models were performed. Post-recurrence OS was analyzed as time from first distant recurrence (DR) until death. The post-recurrence OS model adjusted for both clin/path factors (including DR-free y, DR site) and time-dependent post-DR therapy (chemo, CDK4/6i). RESULTS: 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. DR occurred in 781 pts (377 ET/P, 404 ET alone) with balanced pt/disease characteristics between arms. ET/P had more visceral (46% vs. 36%) and fewer non-visceral (61% vs. 68%) DR compared to ET alone (p=0.03). Unadjusted post-recurrence OS was significantly worse for ET/P vs. ET (median 22.6 vs. 27.9 mo, HR 1.21 (95% CI 1.01-1.46, p=0.04). However, receipt of any post-recurrence CDK4/6i was significantly higher on ET vs. ET/P arms (41% vs. 66%) and time to post-progression CDK4/6i initiation was significantly shorter for those in the ET vs. ET/P arms (HR 0.50, 95% CI 0.41-0.61, p<0.001) adjusting for region, bone/visceral DR type, DR-free time and age. Conversely, time to post-progression chemotherapy initiation was significantly longer for ET alone vs. ET/P arms (HR 1.31, 95% CI 1.07-1.61, p=0.01). However, after adjustment for clinical factors and post-DR treatment, the OS difference was no longer seen (HR 1.05, 95% CI 0.85-1.28, p=0.65). 3-mo landmark analysis showed similar effect on OS after adjusting for CDK4/6i initiation within 3 mo from DR (unadjusted HR 1.24, p=0.03 vs. adjusted HR 1.15, p=0.22). CONCLUSION: The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect. SUPPORT: AFT, ABCSG, NRG, PrECOG; Pfizer