EUROPA Trial

[Slide 1] Articles Single-modality endocrine therapy versus radiotherapy after CrossMark breast-conserving surgery in women aged 70 years and older with luminal A-like early breast cancer (EUROPA): a preplanned interim analysis of a phase 3, non-inferiority, randomised trial Icro Meattini, Maria Carmen De Santis, Luca Visani, Marta Scorsetti, Alessandra Fozza, Bruno Meduri, Fiorenza De Rose, Elisabetta Bonzano, Agnese Prisco, Valeria Masiello, Eliana La Rocca, Ruggero Spoto, Carlotta Becherini, Gladys Blandino, Luca Moscetti, Riccardo Ray Colciago, Riccardo A Audisio, Etienne Brain, Saverio Caini, Marije Hamaker, Orit Kaidar-Person, Matteo Lambertini, Livia Marrazzo, Calogero Saieva, Tanja Spanic, Vratislav Strnad, Sally Wheelwright, Philip M P Poortmans*, Lorenzo Livi*, on behalf of the EUROPA Trial Investigatorst Summary Background Optimal therapy following breast-conserving surgery in older adults with low-risk, early-stage breast Lancet Oncol 2024 cancer remains uncertain. The EUROPA trial aims to compare the effects of radiotherapy and endocrine therapy as Published Online single-modality treatments on health-related quality of life (HRQOL) and ipsilateral breast tumour recurrence (IBTR) December 12, 2024 outcomes in this population. https://doi.org/10.1016/ 51470-2045(24)00661-2 See Online/Comment Methods This non-inferiority, phase 3, randomised study was conducted at 18 academic hospitals across Italy https://doi.org/10.1016/P (17 centres) and Slovenia (one centre). Eligible patients were women aged 70 years or older with histologically "Joint senior authors and study confirmed, stage I, luminal A-like breast cancer, who had undergone breast-conserving surgery and had an coordinators Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to finvestigators are listed in the receive single-modality endocrine therapy or radiotherapy. Endocrine therapy consisted of daily oral aromatase appendix PP 58-59) --- [Slide 2] Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial SYMPOSIUM Trial design OUTIMA AACR Primary end points Phase III trial Exclusive postoperative BTR rate at 5 years (n = 926 patients) RT HRQOL GHS at 2 years BCS w/wo SNB pT1 pN0 (or cN0) 1:1 randomization Follow Up Secondary end points invasive BC LRR, BCSS, and OS CBC ER/PR >10% Adverse events Exclusive adjuvant Ki67 ≤20% HER2- HRQOL QLQ-C30/BR45 ET module domains Age >70 years Europa - systemal good - - - CBC - hereys EUROPA Clinical Trial Gov NCT04134598 Meattini 1, at 30. JGO 2020 I ! - BC cancel 05 19/11 This presentation . the interfectual property of the authoripresemer Contact them - 50% for permission - reprist and/or I --- [Slide 3] SAN ANTONIO PRIMARY ENDPOINT RESULTS - QLQ-C30 GHS score BREAST CANCER SYMPOSIUM Empirical and least square mean change from baseline to 24 months UT Health AACR - - - I I 20 Treatment arm 20 Treatment arm RT arm 15 RT am ET arm 15 ET arm WORSE BETTER GHS mean change from baseline (95% CI) 10 10 5 0 -5 Mean least squares score changes from 5 baseline (95% CI) 0 -5 -10 -10 -15 -20 -15 Baseline 3 months 6 months 12 months 24 months -20 Time since randomization GHS scale RT arm 104 68 92 88 82 ET arm 99 74 79 75 73 QLQ-C30 Actual value Change from baseline Group Visit n Mean SD Mean SD RT arm Baseline 104 71.9 19.1 24 months 82 70.7 20.4 -1.1 18.8 ET arm Baseline 99 75.5 19.3 24 months 74 67.2 23.2 -10.0 25.8 This presentation is the intellectual property of the author/presenter. Contact them at cro for permission to reprint and/or distribute

[Slide 1] RESULTS - ADVERSE EVENTS SAN ANTONIO BREAST CANCER SYMPOSIUM Treatment-emergent adverse events by grade and treatment arm UT Health AACR RT (n = 97) ET (n = 89) Adverse event, n (%) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 >20% AEs Arthralgia (Joint pain) 28 (28.9) 0 0 62 (69.7) 5 (5.6) 1 (1.1) Fatigue 32 (33) 0 0 40 (44.9) 2 (2.2) 0 Breast pain 37 (38.1) 0 0 8 (9) 0 0 Hot flashes 10 (10.3) 0 0 29 (32.6) 2 (2.2) 0 Myalgia (Muscle pain) 13 (13.4) 0 0 28 (31.5) 2 (2.2) 0 Bone pain 23 (23.7) 0 0 25 (28.1) 2 (2.2) 0 Alopecia (Hair loss) 7 (7.2) 0 0 23 (25.8) 0 0 22.5% ET switch Depression 15 (15.5) 1 (1) 0 21 (23.6) 1 (1.1) 0 Insomnia 15 (15.5) 0 0 21 (23.6) 0 0 Osteoporosis 3 (3.1) 0 0 20 (22.5) 0 0 12.4% ET discontinuation Hypercholesterolemia 0 0 0 17 (19.1) 0 0 Vaginal dryness 7 (7.2) 0 0 17 (19.1) 0 0 Irritability 15 (15.5) 0 0 12 (13.5) 1 (1.1) 0 Arthritis 15 (15.5) 0 0 14 (15.7) 0 0 Constipation 14 (14.4) 1 (1) 0 12 (13.5) 1 (1.1) 0 Dermatitis 14 (14.4) 0 0 9 (10.1) 0 0 Weight gain 12 (12.4) 0 0 12 (13.5) 0 0 Headache 9 (9.3) 0 0 10 (11.2) 0 0 9 (9.3) 0 0 9 (10.1) 0 0 Hypertension Data are n (%). The table shows grade 1-2 adverse events occurring in at least 10% of patients in one arm. Occurrences of new primary tumours are not distribute listed This presentation is the intellectual property of the author/presenter Contact them at icro meattini@unifi.it for permission to reprint and/or

[Slide 1] SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER SYMPOSIUM® DECEMBER 10-13, 2024 HENRY B. GONZALEZ CONVENTION CENTER SAN ANTONIO, TX UT Health AACR - - Mays Cancer Comm - DEPARTMENT Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial Icro Meattini, MD University of Florence, Florence, Italy Icro Meattini, Maria Carmen De Santis, Luca Visani, Marta Scorsetti, Alessandra Fozza, Bruno Meduri, Fiorenza De Rose, Elisabetta Bonzano, Agnese Prisco, Valeria Masiello, Eliana La Rocca, Ruggero Spoto, Carlotta Becherini, Gladys Blandino, Luca Moscetti, Riccardo Ray Colciago, Francesca Martella, Lorenzo Vinante, Sara Ramella, Marco Gatti, Sara Pedretti, Patrizia Vici, Nadia G. Di Muzio, Alice Pastorino, Maria Cristina Leonardi, Ivica Ratosa, Jure Verbancic, Riccardo A. Audisio, Etienne Brain, Saverio Caini, Marije Hamaker, Orit Kaidar-Person, Matteo Lambertini, Livia Marrazzo, Calogero Saieva, Tanja Spanic, Vratislav Strnad, Sally Wheelwright, Philip M.P. Poortmans, Lorenzo Livi, on behalf of the EUROPA trial Investigators UNIVERSITA PEuropa DIGLI STUDI FIRENZE --- [Slide 2] DRINGING THE WORLD or EP TOUCTHER SAN ANTONIO BREAST CANCER SYMPOSIUM Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial SYMPOSIUM Trial design Health AACR I - Primary end points Phase III trial Exclusive postoperative - IBTR rate at 5 years (n = 926 patients) - RT HRQOL GHS at 2 years BCS w/wo SNB pT1 pNO (or cN0) 1:1 randomization invasive BC Follow Up Secondary end points - LRR, BCSS, and OS - CBC ER/PR >10% - Adverse events Ki67 ≤20% HER2- Exclusive adjuvant - HRQOL QLQ-C30/BR45 ET Age >70 years module domains Eurapa PROVIDE - - because ******** - inceptar - growth - receptor 2. ****** the spy MICK - relation) - of as = - - - CINC ******* EUROPA - Clinical Trial.Gov NCT04134598 Meattini I, et al. JGO 2020 beaut cave - - - Consumer This presentation a the intellectual property of the author/presenter Contact them at cre measinstonn.ru for permission to reprint and/or distribute --- [Slide 3] SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO PRIMARY ENDPOINT RESULTS - - QLQ-C30 GHS score BREAST CANCER SYMPOSIUM Empirical and least square mean change from baseline to 24 months Health AACR - - - 20 Treatment arm 20 Treatment arm AT am RT am 15 ET arm 15 ET arm WORSE BETTER GHS mean change from baseline (95% CI) 10 10 5 0 -5 Mean least squares score changes from 5 baseline (95% CI) 0 -5 -10 -10 15 -20 -15 Baseline 3 months 6 months 12 months 24 months -20 Time since randomization GHS scale RT am 104 " 92 " 12 ET arm = 14 79 = 13 QLQ-C30 Value p-value Age/G8 adjusted means RT arm 24 months -3.40 0.13 Age/G8 adjusted means ET arm 24 months -9.79 <0.0001 Mean differences RT vs ET 24 months 6.39 0.045 This presentation a the intellectual property of the author/presenter Contact them at for permission to reprint and/or distribute --- [Slide 4] SAN ANTONIO BREAST CANCER SYMPOSIUM Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial SYMPOSIUM Conclusions UT Health AACR - - Summary - interim analysis RT offers better HRQOL GHS preservation than ET at 24 months Lower incidence of treatment-related AEs in the RT arm No warning signals regarding stopping rules Future Directions Ongoing patient recruitment and follow-up Final analysis will include IBTR rates and long-term outcomes Take-Home Message RT or ET may be a viable single-modality treatment option, emphasizing the need for a multidisciplinary and patient-centred personalized care This presentation a the interfectual property of the Contact them at K/B If for permission - reprint and/or distribute

[Slide 1] Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial SYMPOSIUM Trial design OUTIMA AACR Primary end points Phase III trial Exclusive postoperative BTR rate at 5 years (n = 926 patients) RT HRQOL GHS at 2 years BCS w/wo SNB pT1 pN0 (or cN0) 1:1 randomization Follow Up Secondary end points invasive BC LRR, BCSS, and OS CBC ER/PR >10% Adverse events Exclusive adjuvant Ki67 ≤20% HER2- HRQOL QLQ-C30/BR45 ET module domains Age >70 years Europa - systemal good - - - CBC - hereys EUROPA Clinical Trial Gov NCT04134598 Meattini 1, at 30. JGO 2020 I ! - BC cancel 05 19/11 This presentation . the interfectual property of the authoripresemer Contact them - 50% for permission - reprist and/or I --- [Slide 2] SAN ANTONIO PRIMARY ENDPOINT RESULTS - QLQ-C30 GHS score BREAST CANCER SYMPOSIUM Empirical and least square mean change from baseline to 24 months UT Health AACR - I - - - teach Mays Cances Certer 20 Treatment arm 20 RT arm Treatment arm 15 ET arm RT arm 15 ET arm WORSE BETTER GHS mean change from baseline (95% CI) 10 10 5 0 -5 Mean least squares score changes from 5 baseline (95% CI) 0 -5 -10 -15 -10 -20 -15 Baseline 3 months 6 months 12 months 24 months -20 Time since randomization GHS scale RT arm 104 88 92 88 82 ET arm 99 74 79 75 73 QLQ-C30 This presentation is the intellectual property of the author/presenter. Contact them at icro.meattini@unifi.it for permission to reprint and/or distribute. --- [Slide 3] SAN ANTONIO RESULTS - ADVERSE EVENTS BREAST CANCER SYMPOSIUM Treatment-emergent adverse events by grade and treatment arm UT Health AACR - - - May - Code RT (n = 97) ET (n = 89) >20% AEs Adverse event, n (%) Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4 Arthralgia (Joint pain) 28 (28.9) 0 0 62 (69.7) 5 (5.6) 1 (1.1) Fatigue 32 (33) 0 0 40 (44.9) 2 (2.2) 0 Breast pain 37 (38.1) 0 0 8 (9) 0 0 Hot flashes 10 (10.3) 0 0 29 (32.6) 2 (2.2) 0 Myalgia (Muscle pain) 13 (13.4) 0 0 28 (31.5) 2 (2.2) 0 Bone pain 23 (23.7) 0 0 25 (28.1) 2 (2.2) 0 Alopecia (Hair loss) 7 (7.2) 0 0 23 (25.8) 0 0 22.5% ET switch Depression 15 (15.5) 1 (1) 0 21 (23.6) 1 (1.1) 0 Insomnia 15 (15.5) 0 0 21 (23.6) 0 0 Osteoporosis 3 (3.1) 0 0 20 (22.5) 0 0 12.4% ET discontinuation Hypercholesterolemia 0 0 0 17 (19.1) 0 0 Vaginal dryness 7 (7.2) 0 0 17 (19.1) 0 0 Irritability 15 (15.5) 0 0 12 (13.5) 1 (1.1) 0 Arthritis 15 (15.5) 0 0 14 (15.7) 0 0 Constipation 14 (14.4) 1 (1) 0 12 (13.5) 1 (1.1) 0 Dermatitis 14 (14.4) 0 0 9 (10.1) 0 0 Weight gain 12 (12.4) 0 0 12 (13.5) 0 0 Headache 9 (9.3) 0 0 10 (11.2) 0 0 9 (9.3) 0 0 9 (10.1) 0 0 Hypertension Data are n (%). The table shows grade 1-2 adverse events occurring in at least 10% of patients in one arm. Occurrences of new primary tumours are not listed. This presentation is the intellectual property of the author/presenter. Contact them at icro.meattini@unifi.it for permission to reprint and/or distribute.

[Slide 1] Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): a randomized phase 3 trial SYMPOSIUM Current status UT Health AACR - - Italy Alessandria Aviano CRO Brescia Spedali Civili 21 recruiting centres Empoli 858/926 @12Dec24 Candiolo Firenze AOUC Firenze OSMA Genova ISM Milano Istituto Nazionale Tumori Milano Humanitas Cancer Center Milano San Raffaele RADIATION THERAPY ENDOCRING Milano IEO Modena Pavia Roma Campus Biomedico Roma IFO Roma Gemelli Trento Udine Slovenia UNIVERSITA Maribor PEurapa DEGLI STUDI Lubiana FIRENZE - - PRESIDER EUROPA - Clinical Trial.Gov NCT04134598 This presentation is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute. ANTONIO EAST CANCER YMPOSIUM® Health AACR Antonio American Association Cancer Center for Cancer Research --- [Slide 2] Exclusive endocrine therapy or radiation therapy in women aged 70+ years with luminal-like early breast SAN ANTONIO BREAST CANCER cancer (EUROPA): preplanned interim analysis of a randomized phase 3 trial SYMPOSIUM Acknowledgments UT Health AAGR - THE LANCET Oncology Single-modality endocrine therapy versus radiotherapy after Lancet Oncol 2024 breast-conserving surgery in women aged 70 years and older Published Online with luminal A-like early breast cancer (EUROPA): a preplanned interim analysis of a phase 3, non-inferiority, December 12, 2024 randomised trial https://doi.org/10.1016/S1470-2045(24)00661-2 kno Meattini, Marie Commen De Santis, Luca Visanc, Marta Scorsetti, Alessandre Form, Brund Medunl Fiorenze De Rose, Disabette Bonzeno, Agriese Prisco, Valeria Mesicle, (Tione to RICCO, Ruggero Spoto, Carlotta Becherini, Gladys Blanding, Luca Mascetti, Ricordo Ray Cokingo, Riccordo Audisio, [tienne Brain Saverio Coini, Marje Hamaker, Onlt Koidar Person, Mottro Lambertini, Livia Marrazzo, Cologero Saina, Tanja Spenic, Vrobalev Stroad, Sally Wheelwright, Philip Poortmans" Lorenzo M on beholf of the EUROPA Trial investigators! UNIVERSITA Europa DEGLI STUDI FIRENZE EUROPA - Clinical Trial.Gov NCT04134598 - EXERIESCE This presentation is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute SAN ANTONIO BREAST CANCER SYMPOSIUM® UT Health AACR Nan Annonio American Association Mays Cancer Center for Cancer Research