Rapid Fire 5

Y. Y. Tan¹, C. Hu², H. Huang², N. J. Boddicker³, W. Chen³, M. Kaul³, T. J. Rao², A. N. Monteiro⁴, T. Pesaran⁵, R. Karam⁶, S. M. Domchek⁷, S. Yadav⁸, M. E. Richardson⁹, F. J. Couch²; ¹Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, AUSTRIA, ²Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, ³Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, ⁴Department of Epidemiology, H. Lee Moffitt Cancer Center, Tampa, FL, ⁵Genomic Sciences, Ambry Genetics, Aliso Viejo, CA, ⁶Research & Development, Ambry Genetics, Aliso Viejo, CA, ⁷Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, ⁸Department of Oncology, Mayo Clinic, Rochester, MN, ⁹Clinical Research, Ambry Genetics, Aliso Viejo, CA.

Background: Pathogenic variants (PVs) in PALB2 are known to confer high-to-moderate risk for breast cancer. However, breast cancer risk estimates for PALB2 PVs for different populations are not well defined and associations with other cancers are still unclear. Using data from a large clinical genetic testing cohort we have established cancer-specific risks associated with PALB2 PVs. Methods: We analyzed the associations of PALB2 PVs with breast, ovarian, prostate, and pancreatic cancers in individuals tested at Ambry Genetics. Cancer-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated by comparing PV carrier frequencies in cancer cases to population controls from AllofUs matched by sex and adjusting for age and genetic ancestry and gnomAD v4.1 matched by sex and adjusting for ancestry. Two-sided p-values are reported. Results: Of 1,119,667 individuals tested, 357,109 had breast cancer, 37,468 ovarian cancer, 22,112 pancreatic cancer and 32,738 prostate cancer. PALB2 PVs were observed in 0.79% of breast cancer cases, 0.30% of ovarian cancer cases, 0.78% of pancreatic cancer cases, and 0.47% of prostate cancer cases, with mean age at diagnosis of 54.2 years for breast, 60.1 years for ovarian, 62.8 years for pancreatic and 66.7 years for prostate. Whereas only 2.4% of breast cancer cases with PVs had a personal history of ovarian or pancreatic, 13.4% of ovarian cases and 33.3% of pancreatic cases had a history of breast cancer. Analysis of PV types found that frameshift PVs accounted for 50% of PVs, nonsense for 30%, canonical splice sites for 5% and copy number variants for 8-9% of cases in all cancer types. Among 10,077 individuals with multiple primary cancers, PALB2 PVs were detected in 0.65% of cases, with the highest frequencies observed in combinations of breast and pancreatic cancer (1.87%) and pancreatic and prostate cancer (0.79%). To refine estimates of risks for breast cancer, association studies were performed separately with GnomAD v4.1 and AllofUs controls. PALB2 PVs were consistently associated with high risks of breast cancer with lower 95%CI above 4 (GnomADv.4.1 OR=6.85, 95%CI=5.94-7.96, p=3.05×10^-145; AllofUs OR=5.65, 95%CI=4.83-6.65, p=2.54×10^-155). This was significantly different and increased over breast cancer risk estimates from the CARRIERS and BRIDGES population-based studies (OR=4.67, 95%CI=3.73-5.85, p=3.95×10^-27) and the UK Biobank population-based study (OR=3.87, 95%CI=3.09-4.83, p=4.62×10^-27). Similarly, high risks of pancreatic cancer were confirmed (GnomADv.4.1 OR=5.14, 95%CI=4.15-6.32, p=3.38×10^-52; AllofUs OR=5.59, 95%CI=3.92-7.85, p=2.78×10^-18). Importantly, associations between PALB2 PVs and moderate risks of both ovarian cancer (GnomADv.4.1 OR=2.68, 95%CI=2.11-3.40, p=5.94×10^-16; AllofUs OR=2.15, 95%CI=1.62-2.85, p=2.97×10^-7) and prostate cancer (enriched for aggressive disease) (GnomADv.4.1 OR=2.45, 95%CI=2.01-2.97, p=1.52×10^-19) were observed. Conclusions: This large-scale study provides robust estimates of PALB2 PV prevalence and associated cancer risks in a U.S. clinical genetic testing population. The findings provide refined risk estimates for breast and pancreatic cancers but also establish that PALB2 PVs confer increased risk for ovarian and prostate cancers. These results help clarify ongoing uncertainty, particularly for ovarian and prostate cancer, and highlight the importance of PALB2 in broader hereditary cancer risk assessment and multigene panel testing.

E. L. Mayer¹, N. Graham¹, R. A. Leon-Ferre², M. Rozenblit³, C. A. Santa-Maria⁴, S. Isakoff⁵, J. Specht⁶, N. Tung⁷, V. Abramson⁸, J. Desrosiers¹, A. Schubert¹, B. Koca¹, S. M. Tolaney¹, E. P. Winer³, I. E. Krop³, A. C. Wolff⁴, G. I. Shapiro¹, N. Tayob¹, J. L. Guerriero⁹; ¹Dana-Farber Cancer Institute, Boston, MA, ²Mayo Clinic, Rochester, MN, ³Yale University, New Haven, CT, ⁴Johns Hopkins University, Baltimore, MD, ⁵Massachusetts General Hospital, Boston, MA, ⁶Fred Hutchinson Cancer Center, Seattle, WA, ⁷Beth Israel Deaconess Medical Center, Boston, MA, ⁸Vanderbilt-Ingram Cancer Center, Nashville, TN, ⁹Brigham and Women’s Hospital, Boston, MA

BackgroundPARP inhibitors (PARPi) are active in patients (pts) with germline BRCA1/2 or PALB2 mutated (gBRCA1/2; gPALB2m) breast cancer (BC). Preclinical data suggest PARPi leads to intratumoral activation of the proinflammatory cGAS/STING pathway, recruiting CD8+ T cells, and sensitizing gBRCAm cancers to immune-targeted therapy. Prolonged preoperative treatment with PARPi monotherapy has demonstrated notable pathologic complete response (pCR) rates. The randomized phase II TBCRC 056 study evaluates the PARPi niraparib (N) with the anti-PD-1 antibody dostarlimab (D) as neoadjuvant treatment of gBRCAm or gPALB2mHER2-negative BC, with cohorts for both triple negative BC (TNBC, Arms A and B) and estrogen receptor positive (ER+) BC (Arm C). Results from Arms A and B are being presented. MethodsEligible pts (gBRCA1/2m/gPALB2m BC, T >1.0 cm, ER- (<10%), HER2-) were randomized to either Arm A: upfront combination N 200 mg orally QD and D 500 mg IV every 3 weeks (wks) for 18 wks (1 cycle = 3 wks), or Arm B: N monotherapy for 3 wks, followed by combination N plus D for 15 wks, with baseline (BL) and wk 3 tumor biopsies. After 18 wks, pts either underwent surgery or received additional preoperative systemic therapy (per MD choice) after an end of treatment biopsy if residual disease present. The primary study objectives are to evaluate pCR in Arms A and B combined, as well as change in stromal tumor infiltrating lymphocytes (sTILs) from BL to 3 wks in each Arm separately; 46 pts and a target pCR rate of 50% provides 85% power to reject the null hypothesis of pCR < 30%. ResultsA total of 46 pts with TNBC enrolled to Arms A and B (38 gBRCA1m (82.6%), 8 gBRCA2m (17.4%), 0 gPALB2m). Median age was 39.3 years (range 24.8-72.8); 84.8% self-reported White, 6.5% Black, 4.3% Asian, and 8.7% Hispanic. Clinical stage distribution was 37.0% stage I, 45.7% stage II, and 17.4% stage III; most had ER- BC (42 ER <1%, and 4 ER 1-10%). Among all pts, 38 (82.6%) completed the target number of cycles of D, with mean cycles received 5.1. Five pts discontinued D early (3 inadequate response/progression, 2 unacceptable AE: LFTs, rash). A total of 38 pts (82.6%) completed 6 cycles of N, with mean cycles received 5.7. Seven pts discontinued N early (3 inadequate response/progression, 4 unacceptable AE: LFTs, anemia, rash (2)). Most common AEs (> grade 2) with D+N were anemia (26.1%), fatigue (21.7%), hypertension (15.2%), hypothyroidism (15.2%), and neutropenia (15.2%). Most common Grade >3 AEs with D+N were anemia (17%) and neutropenia (6.5%). Among all pts, 23 (50%) had a pCR at surgery (90% CI 37.1% – 62.9%), 12 (26.1%) had residual disease (4 RCB-I, 5 RCB-II, 2 RCB-III, 1 RCB not calculable), and 11 (23.9%) crossed over to additional preoperative therapy. The pCR rate exceeded the protocol efficacy criterion of >43%, a significant increase over null hypothesis. pCR rates were the same on Arms A (50%, 90% CI 31.1% – 68.9%) and B (50%, 90% CI 31.9% – 68.1%). Among 15 pts on Arm A with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 16% (range 1% – 40%), and at 3 wks was 27.4% (range 0.5% – 60%), for an average increase of 11.4% (p=0.009). Among 22 pts on Arm B with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 19.5% (range 1% – 75%), and at 3 wks was 42.1% (range 1% – 85%), for an average increase of 22.7% (p=0.0003). Among all pts, BL sTILs (continuous) were significantly higher among those who achieved pCR than those who did not (median 15% vs. 5%, p=0.03). There was no relationship between pCR and BL PD-L1 score, or pCR and ER-0 vs. ER-low. ConclusionsIn pts with gBRCAm early TNBC, 18 wks of targeted therapy using PARPi and anti-PD1 agents, with or without 3-week PARPi lead-in, resulted in a pCR rate of 50%, and a statistically significant increase in sTILs from BL to 3 wks. Further ongoing correlative work may identify best candidates for this non-chemotherapy-based approach.

N. Tung¹, A. Stradella², A. Brufsky³, P. A. Fasching⁴, J. A. García-Sáenz⁵, S. Paluch-Shimon⁶, F. M. Henao Carrasco⁷, A. Marquez Aragones⁸, T.-W. Park-Simon⁹, S. Antolin Novoa¹⁰, N. Ditsch¹¹, R. Greil¹², M.-P. Graas¹³, N. Harbeck¹⁴, I. Pimentel¹⁵, A. Schneeweiss¹⁶, K.-A. Phillips¹⁷, K. S. Saini¹⁸, M. Dymond¹⁹, X. Liu²⁰, G. Rychlik¹⁹, J. Balmaña²¹; ¹Beth Israel Deaconess Medical Center, Dana-Farber Harvard Cancer Center, Boston, MA, ²Medical Oncology Department, Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain, ³Magee-Women’s Hospital of UPMC, Pittsburgh, PA, ⁴University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany, ⁵Hospital Clínico San Carlos, Madrid, Spain, ⁶Hadassah University Hospital, Jerusalem, Israel, ⁷Hospital Universitario Virgen Macarena, Seville, Spain, ⁸Hospital Universitario Virgen de la Victoria, Malaga, Spain, ⁹Department of Obstetrics and Gynecology, MHH Hannover, Hannover, Germany, ¹⁰Breast Cancer Department, INIBIC, Hospital Universitario de A Coruña, A Coruña, Spain, ¹¹Gynecology, Obstetrics and Senology, Faculty of Medicine, University of Augsburg, Breast Center, University Hospital Augsburg, CCC Alliance WERA, Augsburg, Germany; Bavarian Cancer Research Center (BZKF), Augsburg, Germany, ¹²Hematology and Medical Oncology, Paracelsus Medical University, Salzburg Cancer Research Institute and Cancer Cluster Salzburg, Salzburg, Austria, ¹³CHC Clinique, Liège, Belgium, ¹⁴Department of Obstetrics and Gynecology, Breast Center, LMU University Hospital, Munich, Germany, ¹⁵Department of Oncology, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Catalonia, Spain, ¹⁶National Center for Tumor Diseases, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany, ¹⁷Department of Medical Oncology, Peter MacCallum Cancer Centre and The Sir Peter McCallum Department of Oncology, The University of Melbourne, Victoria, Australia, ¹⁸Fortrea Inc., Durham, NC, ¹⁹Global Medicines Development, Oncology Research and Development, AstraZeneca, Cambridge, United Kingdom, ²⁰Late Development Oncology, Oncology Research and Development, AstraZeneca, Cambridge, MD, ²¹Medical Oncology Department, Hospital Universitari Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain

Background: PARP inhibitors (PARPi) are approved for the treatment of patients with early or advanced breast cancer harboring a germline pathogenic/likely pathogenic variant in BRCA1 and/or BRCA2 (gBRCAm). PARPi, including olaparib, have shown promising activity in the neoadjuvant setting, and the addition of the anti-PD-L1 antibody, durvalumab, may enhance the antitumor immune responses promoted by PARPi. The OlympiaN trial (NCT05498155) was designed to assess the efficacy and safety of neoadjuvant olaparib and olaparib plus durvalumab in stage I and stage II BRCAm HER2-negative breast cancer. Methods: Patients with early-stage BRCAm, estrogen receptor (ER)-negative or -low (≤10%) HER2-negative breast cancer received neoadjuvant olaparib 300 mg BID monotherapy (Cohort A: stage T1b-c/N0) or olaparib 300 mg BID plus durvalumab 1500 mg IV Q4W (Cohort B: stage T2/N0 or T1/N1) for 4-6 cycles, followed by surgery. The primary endpoint was pathological complete response (pCR), defined as ypT0/Tis ypN0, by independent central pathology review (ICPR). Secondary endpoints included residual cancer burden (RCB), tumor volume assessed by magnetic resonance imaging and local radiology review, safety, and tolerability. Patients with pCR by local assessment could continue olaparib post-surgery for a total of 12 cycles of treatment. Patients without pCR received radiation therapy and adjuvant treatment in accordance with local standard of care. Results: At the data cutoff of November 20, 2024, 25 patients had enrolled into Cohort A (5 T1b/N0, 20 T1c/N0; median age 46 years) and 25 had enrolled into Cohort B (all T2/N0; median age 44 years). One patient in Cohort A had a somatic BRCA1 mutation per local testing; all other patients in both cohorts had gBRCAm. In Cohort A, 23 (92%) patients completed 4-6 cycles of neoadjuvant olaparib, 1 (4%) discontinued treatment due to an adverse event (AE; grade 2 neutropenia), and 1 (4%) progressed on treatment; 24 (96%) patients underwent definitive surgery. pCR rate by ICPR was 68% (n=17/25; 95% CI, 47-85%) and 72% (n=18/25; 95% CI, 51-88%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 5 (20%) patients; olaparib-related grade ≥3 anemia occurred in 3 (12%) patients. No deaths occurred during the study period. In Cohort B, 21 (84%) patients completed 4-6 cycles of neoadjuvant olaparib plus durvalumab, 2 (8%) discontinued treatment due to an AE, and 2 (8%) progressed on treatment; 22 (88%) patients underwent definitive surgery with central pathological assessment. pCR rate by ICPR was 80% (n=20/25; 95% CI, 59-93%) and 84% (n=21/25; 95% CI, 64-95%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 6 (24%) patients; olaparib-related grade ≥3 AEs occurred in 3 (12%) patients (1 with anemia, 1 with diarrhea, and 1 with hypersensitivity leading to discontinuation in Cycle 1); 1 patient discontinued olaparib in Cycle 4 following grade 2 nausea and grade 2 dizziness; 1 (4%) had durvalumab-related grade ≥3 diabetes. No deaths occurred during the study period. Conclusions: Neoadjuvant olaparib, alone or in combination with durvalumab, demonstrated high pCR rates (68% and 80%, respectively) in patients with early-stage BRCAm, HER2-negative, ER-negative/-low breast cancer. Safety data were consistent with the known safety profiles of olaparib monotherapy and olaparib plus durvalumab combination therapy. These results encourage future research and development of PARPi therapy in the neoadjuvant setting.

K. B. Fergus¹, K. Ross², M. Scheuner³, B. S. Tong⁴, A. Blanco², A. Fiscalini¹, D. DeRosa⁵, E. Silver⁶, D. Goodman-Gruen⁷, H. Anton-Culver⁸, A. Borowsky⁹, J. Esserman¹⁰, A. Kaster¹¹, A. LaCroix⁵, R. Lancaster¹², A. Naeim¹³, H. Park¹⁴, B. Parker⁵, V. Arasu¹⁵, N. Wenger¹⁶, H. Harvey¹⁷, D. Heditsian¹⁸, S. Brain¹⁸, V. Lee¹⁸, D. Moorehead¹⁹, A. Petruse²⁰, L. Sabacan¹, R. Hiatt³, Y. Shieh²¹, E. Ziv²², O. I. Olopade²³, J. Tice³, M. Eklund²⁴, L. Van ‘T Veer¹, L. J. Esserman¹, L. Madlensky⁵; ¹Department of Surgery, University of California San Francisco, San Francisco, CA, ²Department of Medicine, Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, ³Department of Medicine, University of California San Francisco, San Francisco, CA, ⁴Department of Medicine, Cancer genetics and prevention program, University of California San Francisco, San Francisco, CA, ⁵Department of Medicine, University of California San Diego, San Diego, CA, ⁶Department of Medicine, University of California Los Angeles, Valencia, CA, ⁷Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA, ⁸Department of Medicine, University of California Irvine, Irvine, CA, ⁹Department of Pathology, University of California Davis, Sacramento, CA, ¹⁰Department of OBGYN, Diagnostic Center of Miami, Miami FL USA, Miami, FL, ¹¹Department of Oncology, Edith Sanford Breast Center, Fargo, ND, ¹²Department of Surgery, University of Alabama Birmingham, Birmingham, AL, ¹³Department of Medicine, University of California Los Angeles, Los Angeles, CA, ¹⁴Department of Pathology, University of California Irvine, Irvine, CA, ¹⁵Department of Research, Kaiser Permanente, Pleasanton, CA, ¹⁶Department of General Internal Medicine, University of California Los Angeles, Los Angeles, CA, ¹⁷Department of Medicine, Sanford Health, Sioux Falls, SD, ¹⁸Breast Science Advocacy Core, University of California San Francisco, San Francisco, CA, ¹⁹Women’s Cancer Resource Center, University of California San Francisco, Berkeley, CA, ²⁰Department of Clinical Research, University of California Los Angeles, Los Angeles, CA, ²¹Department of Population Health, Weill Cornell Medicine, New York, NY, ²²Department of General Internal Medicine, University of California San Francisco, San Francisco, CA, ²³Department of Medicine, The University of Chicago, Chicago, IL, ²⁴Department of Surgery, University of California San Francisco, Stockholm, SWEDEN.

Background: The population prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes (BCSG’s) remains largely unknown, in part due to restrictions in genetic testing guidelines. We report early BCSG prevalence estimates from the Women Informed to Screen Depending on Measures of Risk (WISDOM) Trial, where women in the personalized screening arm were offered unrestricted genetic testing, and evaluate the relationship of test positivity to family history and other patient characteristics.Methods: The WISDOM Trial enrolled women without breast cancer between 2016-2023 aged 40-74 in a pragmatic randomized screening trial comparing annual screening mammography to personalized risk-based screening. Participants in the personalized arm were offered germline testing for nine breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, TP53). We report the prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in the sub-population with PVs.Results: Among 23,098 participants who enrolled in the trial and completed genetic testing, 714 (3.1%) carried a PV. After excluding those previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (1.47%) and less common in higher-penetrance BRCA1 (0.14%), BRCA2 (0.36%), and PALB2 (0.19%) variants. PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (<0.1%). Notably, 30% of women with PVs did not report a first- or second-degree female relative with breast or ovarian cancer, a male relative with breast cancer, or Jewish ancestry.Conclusion and Relevance: Unrestricted access to genetic testing in a real-world setting identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under guideline-concordant criteria. These findings support expanding genetic testing to all women as part of personalized breast cancer risk assessment.

I. Pimentel¹, T. Pascual², L. Lema³, P. Tolosa⁴, B. Adamo⁵, M. T. Martínez⁶, I. Blancas⁷, J. Salvador Bofill⁸, J. Ponce⁹, G. Viñas¹⁰, M. Perez-Lopez¹¹, I. Teruel¹², M. González¹³, M. Tapia Céspedes⁶, M. Legerén¹⁴, M. Cejuela Solís⁸, I. Lozano Cubo⁹, X. González Farré¹⁵, J. M. Ferrero-Cafiero¹⁶, A. Llop-Guevara¹⁷, G. Villacampa¹⁸, M. Paes Dias¹⁶, A. Prat², V. Serra¹⁷, J. Balmaña¹⁹; ¹Medical Oncology, Vall d’Hebron University Hospital / Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ²Medical Oncology, Institute of Cancer and Blood Diseases, Hospital Clinic of Barcelona / Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS) / SOLTI Cancer Research Group, Barcelona, SPAIN, ³Medical Oncology, University Hospital 12 De Octubre / Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SPAIN, ⁴Medical Oncology, University Hospital 12 De Octubre / Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12) / SOLTI Cancer Research Group, Madrid, SPAIN, ⁵Medical Oncology, Institute of Cancer and Blood Diseases, Hospital Clinic of Barcelona / Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, SPAIN, ⁶Medical Oncology, Hospital Clínico Universitario de Valencia (INCLIVA), Valencia, SPAIN, ⁷Medical Oncology, Hospital Universitario Clínico San Cecilio / Medicine Department, Granada University / Instituto de Investigación Biosanitaria de Granada (ibs Granada), Granada, SPAIN, ⁸Medical Oncology, Hospital Universitario Virgen del Rocio, Instituto de BioMedicina de Sevilla (IBIS), Sevilla, SPAIN, ⁹Medical Oncology, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, SPAIN, ¹⁰Precision Oncology Group (OncoGIR-Pro), Institut d’Investigació Biomèdica de Girona (IDIBGI) / Medical Oncology, Catalan Institute of Oncology, Hospital Universitari Dr. Josep Trueta, Girona, SPAIN, ¹¹Medical Oncology, CHUAC – Complexo Hospitalario Universitario A Coruña, A Coruña, SPAIN, ¹²Medical Oncology, Institut Català d’Oncologia Badalona (ICO Badalona), Institut Català d’Oncologia Badalona (ICO Badalona), Hereditary Cancer Program, B-ARGO/CARE program, (IGTP) Hospital Germans Trias i Pujol, Badalona, SPAIN, ¹³Medical Oncology, University Hospital of Badajoz, Badajoz, SPAIN, ¹⁴Medical Oncology, Hospital Universitario Clínico San Cecilio / Instituto de Investigación Biosanitaria de Granada (ibs Granada), Granada, SPAIN, ¹⁵Medical Oncology, IOR – Instituto Oncologico Dr. Rosell, Hospital General de Catalunya / SOLTI Cancer Research Group, Barcelona, SPAIN, ¹⁶Clinical Research, SOLTI Cancer Research Group, Barcelona, SPAIN, ¹⁷Experimental Therapeutics Group, Vall D’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ¹⁸Clinical Research, SOLTI Cancer Research Group / Statistics Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ¹⁹Medical Oncology, Vall d’Hebron University Hospital / Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN.

Background: PARP inhibitors (PARPi) improve outcomes in early and advanced HER2-negative (HER2-) breast cancer patients (pts) harboring a germline BRCA1/2 (gBRCA) pathogenic variants (PVs). However, gBRCA alone does not capture all tumors with homologous recombination deficiency (HRD), such as those with epigenetic silencing or other homologous recombination repair (HRR) gene alterations. We previously developed a functional HRD biomarker based on tumor RAD51 nuclear foci, validated retrospectively in early-stage BC (EBC) pts (GeparSixto and GeparOla trials). To date, no prospective study has assessed the predictive value of the RAD51 test for PARPi sensitivity. Methods: SOLTI-RADIOLA trial (NCT0534041) is a multicenter, open-label, two cohorts phase II study in pts with HER2- metastatic BC (mBC) with ≤ 2 prior lines of chemotherapy. Cohort 1(C1) included pts with known germline or somatic PVs in BRCA1/2, PALB2, or RAD51C/D. Cohort 2 (C2) included pts without/unknown HRR PVs but classified as HRD based on RAD51. RAD51 test was performed on pre-treatment tumor samples. HRD was defined as ≤10% RAD51-positive cells (RAD51-low). All pts received olaparib 300 mg BID until progression or unacceptable toxicity. Primary endpoint was overall response rate (ORR) by RECIST v1.1 in C1. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR) and safety. The study was designed to have 90% power to detect differences in the ORR between RAD51-low and -high tumors in C1. Results: From April 2022 to June 2024, 86 pts were screened in C1 and 278 in C2 (RAD51-low: C1- 45/67 [67.2%]; C2 – 17/201 [8.5%]), and 65 were enrolled (C1: n=55; C2: n=10). The median follow-up time was 6.8 months (mo). At the data cut-off, 6 pts (9.2%) remained on treatment. Most pts were female (96.9%), post-menopausal (74.6%), had HR-positive disease (58.5%), visceral metastases (84.3%) and received previous systemic treatment for mBC (89.2%). In C1, 96.3% had germline PVs (BRCA2: 43.6%, BRCA1: 40.0%, PALB2: 14.6%, RAD51D: 1.8%) and 3.7% had somatic PVs. Among C1 pts, 74.5% (n=41) were RAD51-low and 25.5% (n=14) RAD51-high. In C1, the ORR was significantly higher in RAD51-low vs RAD51-high tumors (68.3% vs 21.4%; OR = 7.90, 95%CI 2.07-39.54; p=0.002). PFS was longer in the RAD51-low group (7.1 vs 5.6 mo; hazard ratio = 0.51, 95% CI 0.26-0.98). In C2, the ORR was 10.0%, the 12-mo PFS rate was 30.0% (95%CI 11.6 – 77.3). Treatment-related toxicity led to dose reduction in 12.3% of pts. Conclusion: Our results demonstrate that the RAD51 assay enriches for PARPi response in pts with HRR PVs. These findings are especially relevant in EBC, where HRD is more frequent, supporting broader and more precise use of PARPi-based therapies.

P. R. Pohlmann¹, H. S. Rugo², C. Yau³, D. Yee⁴, A. J. Chien³, N. O. Williams⁵, A. M. Wallace⁶, J. C. Boughey⁷, C. Vaklavas⁸, M. Arora⁹, V. Borges¹⁰, A. S. Clark¹¹, C. Omene¹², C. Isaacs¹³, E. Stringer-Reasor¹⁴, R. Nanda¹⁵, C. Falkson¹⁶, K. S. Albain¹⁷, N. Chan¹⁸, E. T. Roussos Torres¹⁹, M. Rozenblit²⁰, J. Tseng², S. Bommakanti²¹, C. Nangia²², L. Brown-Swigart³, G. L. Hirst³, N. Pasricha³, C. H. Kretzer³, J. Perlmutter²³, A. Borowsky³, W. F. Symmans¹, L. van ‘t Veer³, N. Hylton³, L. J. Esserman³; ¹University of Texas MD Anderson Cancer Center, Houston, TX, ²City of Hope, Duarte, CA, ³University of California San Francisco, San Francisco, CA, ⁴University of Minnesota Masonic Cancer Center, Minneapolis, MN, ⁵Ohio State University Comprehensive Cancer Center, Columbus, OH, ⁶University of California San Deigo, San Diego, CA, ⁷Mayo Clinical Comprehensive Cancer Center, Rochester, MN, ⁸University of Utah Huntsman Cancer Institute, Salt Lake City, UT, ⁹Universiy of California Davis Comprehensive Cancer Center, Sacramento, CA, ¹⁰University of Colorado Anschutz Medical Campus, Arora, CO, ¹¹University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, ¹²Rutgers Cancer Institute, New Brunswick, NJ, ¹³Georgetown University Lombardi Cancer Center, Washington DC, DC, ¹⁴The University of Alabama at Birmingham, Birmingham, AL, ¹⁵University of Chicago Medicine, Chicago, IL, ¹⁶University of Rochester Medicine Wilmot Cancer Institute, Rochester, MN, ¹⁷Stritch School of Medicine of Loyola University Chicago, Chicago, IL, ¹⁸New York University Langone Health, New York, New York, NY, ¹⁹University of Southern California Keck School of Medicine, Los Angeles, CA, ²⁰Yale University, New Haven, CT, ²¹Hennepin County Medical Center, St. Louis Park, MN, ²²HOAG Memorial Hospital Presbyterian, Irvine, CA, ²³The Gemini Group, Ann Arbor, MI

Background I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) in the neoadjuvant breast cancer (BC) setting, evaluating novel regimens in Block A, followed by standard therapies in Blocks B/C if indicated. Therapy in Block B is guided by tumor Response Predictive Subtype (RPS; Wolf, Cancer Cell 2022), which integrates immune, DNA repair, and luminal gene expression signatures with HR and HER2 status, classifying BC into 6 subtypes. ARX788 is an anti-HER2 Antibody Drug Conjugate (ADC) with site-specific conjugation of the noncleavable tubulin polymerization inhibitor Amberstatin (AS269). Patients (pts) with RPS S5 (HER2+/non-Luminal) and S6 (HER2+/Luminal) were eligible for assignment to ARX788 Q3W x 4 cycles in Block A. The primary endpoint was pCR following investigational Block A or after the entire therapy sequence. Methods Pts underwent serial MRI scans during therapy. Projected responders after Block A or B could proceed to surgery early, while others continued to Blocks B/C, which included TCHPx6 or THP±AC. Efficacy of ARX788 followed by surgery was evaluated using a Bayesian covariate-adjusted model estimating pCR and compared to fixed subtype-specific thresholds. To estimate pCR rate in the context of a multi-decision treatment regimen (Blocks A/B/C), we estimated pCR using a Bayesian model that considers timing of pCR and compares rates to a subtype-specific Dynamic Control (DC) modeled from I-SPY data (N=1,818). Results From Sep 2022 to Dec 2024, 100 pts were randomized to ARX788. In sequence with chemotherapy, 63/100 pts achieved pCR, and 82/100 had RCB 0/1, all without AC. Notably, 40 pts proceeded to surgery after Block A alone; of these, 33 (82%) had RCB 0/1, avoiding prolonged conventional chemotherapy. The RPS S6 (HER2+/Luminal) subgroup had a pCR rate of 39%, compared to a 17% DC rate, exceeding the predefined probability threshold of superior pCR rate to DC. Receptor status alone did not correlate with efficacy, emphasizing the importance of molecular subtyping in treatment selection. There were no RCB-3 cases. Ocular toxicity was reported in 95% of patients (9% grade 3), and pneumonitis in 6% (2% grade 3), with no treatment related deaths. 8 pts did not complete all planned ARX788 due to adverse events. The results for ARX788 as a stand-alone therapy or sequential strategy are summarized in the Table. Conclusions The sequential combination of ARX788 with chemo/anti-HER2 therapy demonstrated high efficacy, particularly in the HER2+/Luminal subtype compared to DC, suggesting that a significant proportion of pts could avoid prolonged chemotherapy. Ongoing studies are underway to define and implement strategies to prevent treatment associated ocular toxicity. I-SPY2.2 validates the use of personalized neoadjuvant therapy guided by molecular diagnostics and response-adaptive strategies tailored to each individual patient. NCT01042379