Abstract: BACKGROUND Endocrine therapies (ETs) that target estrogen receptor (ER) activity and/or estrogen synthesis are the mainstay of ER+ breast cancer (BC) treatment. Despite best management, ≤20% of patients (pts) with ER+/HER2– early BC (eBC) develop resistance (in some cases due to acquisition of tumor mutations in ESR1 that can drive estrogen-independent transcription and proliferation) and still have high recurrence rates on standard ETs. New treatment alternatives for ER+/HER2– eBC are needed to reduce risk of recurrence and improve survival, tolerability, quality of life, and adherence. Giredestrant, a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD), achieves robust ER occupancy and is active against tumors that retain ER-sensitivity or have ESR1 mutation(s). It has been demonstrated to be more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant, the only currently approved SERD. Early-phase clinical studies have demonstrated that single-agent giredestrant (30 mg daily) has promising clinical and pharmacodynamic activity and is well tolerated in the ER+/HER2– eBC and metastatic BC settings. TRIAL DESIGN This is a phase III, global, randomized, open-label, multicenter study evaluating efficacy and safety of adjuvant giredestrant vs physician’s choice of adjuvant ET (PCET) in pts with medium- and high-risk stage I–III histologically confirmed ER+/HER2– eBC. Pts are randomized 1:1 to oral 30 mg daily giredestrant or PCET (tamoxifen, anastrozole, letrozole, or exemestane, given according to prescribing information). Stratification factors are risk (medium vs high, based on anatomic [tumor size, nodal status] and biologic features [grade, Ki67, gene signatures if available] ); geographic region (US/Canada/Western Europe vs Asia-Pacific vs rest of the world); prior chemotherapy (no vs yes); and menopausal status (pre-/perimenopausal vs postmenopausal). Beginning on Day 1 of Cycle 1, pts will be treated with giredestrant or PCET for ≥5 years. Continuing PCET after 5 years is at discretion of the investigator and per local standard of care. ELIGIBILITY Female/male pts with medium-/high-risk stage I–III ER+/HER2– eBC; prior curative surgery; completion of (neo)adjuvant chemotherapy (if administered) and/or surgery & lt; 12 months prior to enrollment; no prior ET (≤4 weeks of [neo]adjuvant ET is allowed). For men and pre-/perimenopausal women, a luteinizing hormone-releasing hormone agonist will be given per local prescribing information (mandatory for pts in the giredestrant arm). AIMS Primary endpoint: Invasive disease-free survival (IDFS). Secondary endpoints: Overall survival; IDFS (STEEP definition, including second non-primary BC); disease-free survival; distant recurrence-free survival; locoregional recurrence-free interval; safety; pharmacokinetics; pt-reported outcomes. In addition, this study aims to improve health equity in research and expand clinical trial access. The study will also use/develop digital healthcare solutions, which will enable better understanding of pts’ needs and their adherence to ET. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim analysis and a futility analysis are planned, and an independent data monitoring committee will be in place. ACCRUAL 1018/4100 pts have been recruited globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04961996. AB, PS and CG contributed equally. This abstract was originally presented at SABCS 2021 (OT2-11-09). a & gt;Disclosure(s): Peter Schmid, MD, PhD: Astellas Pharma: Contracted Research (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Boehringer Ingelheim: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffmann-La Roche Ltd.: Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Contracted Research (Ongoing); Medivation Inc.: Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); OncoGenex: Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Puma Biotechnology: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing) Charles E. Geyer Jr, MD, FACP: Abbvie: Contracted Research (Terminated, July 1, 2022), Writing assistance (Terminated, July 1, 2022); AstraZeneca: Contracted Research (Ongoing), Writing assistance (Ongoing); Daiichi/Sankyo: Contracted Research (Ongoing); Exact Sciences: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffman-La Roche Ltd: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche) (Ongoing); Genentech: Contracted Research (Ongoing), Writing assistance (Ongoing) Nadia Harbeck, MD, PhD: Amgen: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Exact Sciences: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pierre Fabre: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Sandoz: Consulting Fees (e.g., advisory boards) (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); WSG: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing) Mothaffar Rimawi, MD: Daiichi Sankyo: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Macrogenics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Contracted Research (Ongoing); Seattle Genetics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Sara Hurvitz, MD, FACP: Ambrx: Contracted Research (Ongoing); Amgen: Contracted Research (Ongoing); Arvinas: Contracted Research (Ongoing); Astra Zeneca: Contracted Research (Ongoing); Bayer: Contracted Research (Ongoing); Cytomx: Contracted Research (Ongoing); Daiichi-Sankyo: Contracted Research (Ongoing); Dignitana: Contracted Research (Ongoing); Eli Lilly: Contracted Research (Ongoing); Genentech/Roche: Contracted Research (Ongoing); Gilead: Contracted Research (Ongoing); GSK: Contracted Research (Ongoing); Ideal Implant: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing); Immunomedics: Contracted Research (Ongoing); Macrogenics: Contracted Research (Ongoing); Novartis: Contracted Research (Ongoing); OBI Pharma: Contracted Research (Ongoing); Orinove: Contracted Research (Ongoing); Pfizer: Contracted Research (Ongoing); Phoenix Molecular Designs, Ltd.: Contracted Research (Ongoing); Pieris: Contracted Research (Ongoing); PUMA: Contracted Research (Ongoing); Radius: Contracted Research (Ongoing); Sanofi: Contracted Research (Ongoing); Seattle Genetics/Seagen: Contracted Research (Ongoing); Zymeworks: Contracted Research (Ongoing) Miguel Martín, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche: Third-party writing assistance for this abstract, furnished by Eleanor Porteous, MSc, of Health Interactions, was provided by Roche (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Lilly/ImClone: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pierre Fabre: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing) Sherene Loi, MBBS (Hons), PhD, FRACP, FAHMS, GAICD: Aduro Biotech, Inc.: Consulting Fees (e.g., advisory boards) (Ongoing); Akamara Therapeutics: Uncompensated scientific advisory board member (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); BMS: Uncompensated consultant (Ongoing); Breast Cancer Research Foundation, New York: Supported by the Breast Cancer Research Foundation, New York (Ongoing); G1 Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing); GlaxoSmithKline: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Uncompensated consultant (Ongoing); National Breast Cancer Foundation of Australia Endowed Chair: Supported by the National Breast Cancer Foundation of Australia Endowed Chair (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); Roche-Genentech: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing), Uncompensated consultant (Ongoing); Seattle Genetics: Uncompensated consultant (Ongoing); Silverback Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing) Shigehira Saji, MD, PhD: Astra Zeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Bayer: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Boerhringer-ingelheim: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Breast International Group: Executive board member (Ongoing); Chugai: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eisai: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Japan Breast Cancer Research Group: Executive board member (Ongoing); Japanese Breast Cancer Society: Executive board member (Ongoing); Japanese Society of Medical Oncology: Executive board member (Ongoing); Kyowa Kirin: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Nihonkayaku: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Ono: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Taiho: Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Takeda: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Kyung Hae Jung, MD, MS, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi-Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); Everest Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Takeda: Consulting Fees (e.g., advisory boards) (Ongoing) Gustavo Werutsky, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Contracted Research (Ongoing); Beigene: Contracted Research (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); GSK: Contracted Research (Ongoing); Lilly: Contracted Research (Ongoing), Honoraria (Ongoing); MSD: Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Seattle Genetics: Contracted Research (Ongoing) Daniil L. Stroyakovsky, MD: Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Vanesa López-Valverde, PharmD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Michael Davis, PsyD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Tanja Badovinac Crnjevic, MD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Pablo D. Perez-Moreno, MD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Aditya Bardia, MD, MPH: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); BioTheranostics: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Foundation Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Immunomedics/Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Phillips: Consulting Fees (e.g., advisory boards) (Ongoing); Radius Health: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing) & lt;/a & gt; Citation Format: Peter Schmid, Charles E. Geyer Jr, Nadia Harbeck, Mothaffar Rimawi, Sara Hurvitz, Miguel Martín, Sherene Loi, Shigehira Saji, Kyung Hae Jung, Gustavo Werutsky, Daniil L. Stroyakovsky, Vanesa López-Valverde, Michael Davis, Tanja Badovinac Crnjevic, Pablo D. Perez-Moreno, Aditya Bardia. lidERA Breast Cancer: A phase III adjuvant study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy in patients with estrogen receptor+, HER2– early breast cancer [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 OT2-03-02.

Abstract: Background: In trials of HER2+ metastatic breast cancer (mBC), trastuzumab deruxtecan (T-DXd) monotherapy showed durable efficacy (DESTINY-Breast01) and significantly prolonged progression-free survival vs trastuzumab emtansine (DESTINY-Breast03). T-DXd is approved in the US for patients with HER2+ unresectable/mBC who received ≥1 prior anti-HER2–based treatment (tx) in the metastatic or neo-/adjuvant setting and recommended for approval in the EU as 2nd-line tx. Preclinical data suggest that T-DXd used in combination with other anticancer tx may lead to improved efficacy. The purpose of DB-07 is to assess the safety and efficacy of T-DXd alone or with other anticancer tx for patients with HER2+ mBC. Here we report preliminary data from the DB-07 dose-expansion phase for T-DXd monotherapy and T-DXd + pertuzumab (P) as 1st-line (1L) tx in mBC. Methods: DB-07 (NCT04538742) is an ongoing, phase 1b/2, 2-part (part 1: dose finding; part 2: dose expansion), modular, open-label trial of T-DXd alone or with other anticancer tx in patients with HER2+ mBC. In part 2, patients in module (mod) 0 received T-DXd 5.4 mg/kg every 3 weeks (Q3W) and in mod 2, T-DXd 5.4 mg/kg + P 420 mg Q3W (loading dose: 840 mg), the recommended phase 2 dose. Patients in these mods must be mBC tx naive. For part 2, the primary objective is to assess safety and tolerability. A secondary objective is to assess the objective response rate (ORR) per local investigators by Response Evaluation Criteria In Solid Tumors v1.1. We report results for patients randomized before Oct 13, 2021 to mods 0 and 2 of part 2 (data cutoff [DCO]: Mar 4, 2022); recruitment is ongoing. Based on the distinct mechanism of action of T-DXd and P, we conducted preclinical studies with the drugs in HER2-overexpressing cell lines to elucidate their potential synergies. To assess the effects on T-DXd internalization, live cell imaging was performed using pH-dependent fluorescently labeled T-DXd. To assess the effects on HER2 signaling, total and p-HER2 levels and downstream substrates were evaluated by immunoblot. Results: 23 patients were enrolled in the T-DXd monotherapy mod; 20 (87.0%) were receiving tx and 3 (13.0%) discontinued tx (withdrawal by patient, n=2; adverse event [AE], n=1) by DCO. 22 patients were enrolled in the T-DXd + P mod; 20 (90.9%) were receiving tx and 2 (9.1%) discontinued tx (AE, n=1; disease progression, n=1) by DCO. All patients experienced AEs (Table); 1 patient in each mod died. The unconfirmed ORR (80% CI) with T-DXd monotherapy and T-DXd + P was 82.6% (68.2%-92.2%) and 77.3% (61.9%-88.5%), respectively; updated data will be presented. Preclinical studies showed that T-DXd was more rapidly and effectively internalized in combination with P than when administered alone. Immunoblotting of cell lysates showed a greater reduction in total HER2 and HER2 signaling in response to combination tx than with T-DXd or P alone. Discussion: In summary, 1L T-DXd monotherapy and T-DXd + P safety profiles and antitumor activity were consistent with those previously reported for T-DXd. Mature data in these mods are awaited, and other T-DXd combinations are being investigated in additional mods. Preclinical studies showed the potential for P to induce greater internalization of T-DXd and inhibition of HER2-driven signaling. These results support investigation of T-DXd in larger ongoing trials (eg, NCT04784715). Table 1: Summary of treatment duration and safety data Citation Format: Erika Hamilton, Komal Jhaveri, Sherene Loi, Carey Anders, Peter Schmid, Konstantin Penkov, Elena Artamonova, Lyudmila Zhukova, Daniil L. Stroyakovsky, Dinesh Chandra Doval, Rafael Villanueva, Flavia Michelini, Sarat Chandarlapaty, Matt Wilson, Sarice R. Boston, Adam Konpa, Shoubhik Mondal, Fabrice Andre. Dose-Expansion Study of Trastuzumab Deruxtecan as Monotherapy or Combined With Pertuzumab in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Breast Cancer in DESTINY-Breast07 (DB-07) [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 PD18-11.