Abstract Background Breast cancer (BC) is a clinically and biologically heterogenous disease where intrinsic subtypes play a role. Non-luminal subtypes within HR+/HER2-negative disease do not benefit to the same extent from standard of care treatments as the luminal subtypes. Thus, other strategies are needed. HER2-E subtype represents approximately 15.0% of HR+/HER2-negative tumors in metastatic setting. According to an exploratory analysis of EGF30008 trial, HER2-E advanced BC patients, despite presenting poor outcomes across treatments, showed benefit from anti-HER2 therapy with lapatinib. Here, we report the efficacy and safety of the NEREA trial, the first study designed to evaluate neratinib and endocrine therapy in HR+/HER2-negative, PAM50 HER2-E ABC. Methods SOLTI-1718 NEREA (NCT04460430) is a single-arm, multicenter phase II study evaluating neratinib in combination with endocrine therapy (ET) in patients with HR+/HER2-, PAM50 HER2-E ABC. Key inclusion criteria include progression to prior endocrine therapy, ≤ 1 line of chemotherapy for advanced breast cancer (ABC), ECOG 0-1, and HER2-E disease by PAM50 on a metastatic tumor biopsy. The availability of a metastatic tumor sample was mandatory in the pre-screening phase to assess PAM50 subtype. Included patients received neratinib 240 mg daily in combination with ET, with either exemestane, fulvestrant or tamoxifen (as per investigator´s decision). All patients received prophylactic loperamide with an established dosing scheme during the first cycle and on-demand in subsequent cycles. The primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary endpoints include other efficacy endpoints and safety. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 14 of 33 patients achieved PFS > 6m. In that case, the trial would recruit up to 56 patients for a target PFS6 ≥ 50%. Results. Between July 2020 and June 2022, molecular subtyping was performed on tumors from 136 patients, and 18 HER2-E tumors were identified (7.6%). 12 evaluable patients were enrolled. Baseline characteristics were as follows: median age 60 years, 91.7% of pts were postmenopausal, 75% had visceral disease and 59% received (neo)adjuvant treatment. The median number of lines for ABC was 3 (1-5). Neratinib was combined with exemestane (41.7%), fulvestrant (33.8%) and tamoxifen (25%). At the time of data cut-off (June 2023), 9 patients (75%) had stopped their treatment because of PD and 2 (16.7%) due to toxicity. The PFS6 months occurred in one patient (8.3%, CI: 0.2% - 38.5%). Median PFS was 1.7 months (95% CI 1.6-1.9) with a patient still on treatment after 27.1 months. The incidence of treatment-related adverse events (trAEs) was 25%; diarrhea (25%), asthenia (16.7%), nausea (8.3%), vomiting (8.3%) and rash (8.3%) were most common and were predominantly grade 1/2. 25% of patients experienced grade 3 trAEs. Conclusions.Due to slow enrollment, the study was stopped early. At the time of study close, the hypothesis that neratinib has efficacy in HR+/HER2-, PAM50 HER2-E tumors was not confirmed. We thank PUMA BIOTECHNOLOGY, INC for their provision of Neratinib and financial contribution to the study. Citation Format: Eva Ciruelos, Cristina Saura, Xavier Gonzalez-Farré, Francisco Javier Salvador Bofill, Maria Vidal, Isabel Blancas, Elena López-Miranda, Maria Iglesias, Míriam Arumí, Mireia Margelí, Catarina Pulido, Serafin Morales Murillo, Fernando Henao, Pilar Sanchez, Sara Alves, Ana Godoy Ortiz, José Passos Coelho, Santiago Escrivá-de-Romaní, Alejandra Espinosa, Tomás Pascual, Aleix Prat. SOLTI-1718 NEREA Trial: Neratinib in hormone receptor (HR)-positive/HER2-negative HER2-enriched (HER2-E) advanced breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-07.

Abstract Background. Premenopausal women diagnosed with HR+/HER2- breast cancer (BC) often have a different biology and worse prognosis. The SOFT and TEXT studies demonstrated an increase diseasefree survival (DFS) with ovarian function suppression (OFS) plus tamoxifen or exemestane compared to tamoxifen alone. Of note, high-risk clinicopathologic features, adjuvant chemotherapy, or aged ≤35 years correlated with greater OFS benefit. However, adding OFS in this context has intrinsic issues as higher toxicity, which led to treatment discontinuation (20% in SOFT trial), and suboptimal OFS was found in around 25% of patients (pts) with exemestane plus monthly triptorelin (SOFT-EST sub-study). Thus, new effective ET options without OFS are needed for premenopausal patients (pts). Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy to SOC treatments and specifically compared to fulvestrant in postmenopausal pts with HR+/HER2- metastatic BC at the phase III EMERALD trial. In menopausal patients with HR+/HER2- early BC, the window of opportunity SOLTI-1905 ELIPSE trial (NCT04797728), showed that elacestrant was associated with a 27.3% rate of Complete Cell Cycle Arrest (CCCA) and a statistically significant suppression of Ki-67. Among Luminal A tumors, the CCCA rate was 45% and the average decrease in Ki-67 was 64.6%, while no CCCA was reported and the suppression of Ki-67 was less pronounced (31.7%) in the Luminal B population. There is still a need for investigating elacestrant without OFS in the premenopausal scenario. We hypothesize that elacestrant as a single agent or in combination with triptorelin is an effective and safe treatment regimen in premenopausal pts with HR+/HER2-negative early BC capable of achieving an equivalent CCCA rate as a subrogate of effectiveness regardless the use of OFS Study design. PREMIERE is a parallel, non-comparative, two-arm, randomized 1:1, open-label, multicenter, exploratory study in premenopausal women with primary operable HR+/HER2-negative BC. The study aims to evaluate the biological effects of elacestrant with or without triptorelin. Participants must have histologically confirmed HR+ (≥ 10%) and HER2- operable early BC stage I to stage IIB >1 cm with a Ki-67 between 10-35%. The primary objective is to assess the ability of each treatment arm to induce CCCA determined by central assessment of Ki-67 (% Ki-67 ≤ 2.7%). No formal comparison between treatment arms is intended. Secondary objectives include evaluating the biological activity of elacestrant with or without OFS, antiproliferative activity, changes in gene expression including PAM50 subtype changes, and the effect of optimal vs suboptimal suppression on CCCA . Serum E2 and FSH levels will also be evaluated. Safety and tolerability will be assessed based on adverse events and clinical laboratory test results. Pts will undergo screening and randomization, with stratification by PAM50 subtype (Luminal A vs Non-luminal A). Treatment will be elacestrant 400 mg once daily or elacestrant 400 mg once daily plus triptorelin 3.75 mg days +1 and +29 for 30 (+7) days. Surgery or biopsy will be performed after treatment completion, and a post-surgery visit will mark the end of the active follow-up period. Patients will receive SOC treatment after surgery. 48 patients will be recruited in 9 sites within SOLTI Spanish network in 9 months period. This study is financially supported by Menarini-Stemline. Citation Format: Meritxell Bellet- Ezquerra, Cristina Hernando, Pablo Tolosa, Maria Vidal, Yolanda Fernández, Santiago González-Santiago, Pilar Sanchez, Susana De La Cruz, Vanesa Ortega, Xavier Gonzalez-Farré, Milana Bergamino, Alejandra Espinosa, Tomás Pascual. A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-08.

Abstract Background: Hormone Receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (BC) is a highly heterogenous disease. Non-luminal subtypes within HR+/HER2- BC have been linked to poor survival in the metastatic setting. However, these subtypes might exhibit higher expression of immune-related genes, tumor-infiltrating lymphocytes (TILs), and APOBEC signatures. This study aimed to investigate the presence of tertiary lymphoid structures (TLS), TILs and immune gene expression (GE) across PAM50 intrinsic subtypes (IS) in metastatic samples from patients (pts) with HR+/HER2- BC. Methods: We included pts with HR+/HER2- metastatic BC who participated in the molecular prescreening of the SOLTI-1904-ACROPOLI (NCT04802876), SOLTI-1502-ARIANNA (NCT04142060), SOLTI-1718-NEREA (NCT04460430) and SOLTI-1716-TATEN (NCT04251169) studies, providing metastatic samples for analysis. The proportion of TILs was centrally evaluated by a single pathologist using standard criteria. GE analysis was performed on the same FFPE tumor block using a panel of 72 genes, including 10 immune genes and the PAM50 IS. In a subset of patients, we conducted additional GE analysis using a panel of 192 genes, including the 14-gene B-cell/IgG (IGG) signature, while also retrospectively assessing the presence of TLS. Descriptive statistics, significance analysis of microarrays (using False Discovery Rate [FDR]) and logistic regressions were used to investigate the association between TLS, TILs, immune GE and PAM50 IS. Results: A total of 401 pts were included. Distribution across IS was: 53.4% Luminal B (n=197), 27.1% Luminal A (n=100), 16% HER2-enriched (n=59), 2.7% basal-like (n=10) and 0.8% normal-like (n=3). TILs were evaluated in 375 samples (93.5%). Median (m) TILs proportion was 2% (IQR: 1-4, range 0-80). Non-luminal subtypes exhibited a higher enrichment of TILs compared to luminal subtypes (m=3% vs m=1%, p=0.002). Moreover, significant differences of TILs were also seen according to the site of metastasis (M1): m=6.5% in lymph nodes vs m=4.5% in lung M1 vs m=1% in liver M1 (p< 0.001). Immune GE was significantly higher in samples with a high proportion of TILs ( >10%), although the correlation between TILs and immune genes was moderate (e.g, coefficient=0.44, p< 0.001, between CD8A and TILs). TLS were evaluated in 147 samples and detected in 16 pts (10.9%). Compared to TLS-negative tumors, TILs were significantly higher in TLS-positive (TLS+) tumors (m=1.5% vs m=10%, p< 0.001). In addition, the presence of TLS was significantly higher in non-luminal subtypes compared to luminal subtypes (18% (11/61) vs 5.8% (5/86), p=0.019). TLS+ tumors had a significant enrichment of genes related to activated B-cells (CD19, CD79A), plasma cells (CD27), immunoglobulins (IGKC, IGLV), and T-cells (CD8A, PDCD1). Notably, the IGG signature as a continuous variable demonstrated a significant association with TLS presence, independently of the PAM50 IS and TILs (p=0.033, ROC AUC=0.817). Finally, higher expression of some immune genes was observed in non-luminal subtypes vs luminal subtypes (e.g., CD19 (p=0.016) and CD274/PDL1 (p< 0.001)). Conclusions: Our translational analysis reveals that non-luminal subtypes within metastatic HR+/HER2- BC exhibit a higher enrichment of TILs, immune GE, and presence of TLS. Importantly, we identified the IGG signature as a robust immune GE pattern that is strongly associated with TLS across PAM50 IS, independent of TILs. These findings highlight the potential significance of the IGG signature as a novel biomarker for precisely measuring TLS and selecting pts who might be more likely to derive benefit from immunotherapy. Citation Format: Elia Seguí, Esther Sanfeliu, Fara Brasó-Maristany, Blanca González-Farré, Fernando Salvador, Laura Angelats, Lorea Villanueva, Alejandra Espinosa, Patricia Galván, Esther Fernández, Xavier Gonzalez-Farré, Santiago Escrivá-de-Romaní, Núria Chic, Eva Ciruelos, Cristina Saura, Luis Manso, Mafalda Oliveira, Josep Tabernero, Aleix Prat, Tomás Pascual. Characterizing Immune Infiltration in Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer: A Comprehensive Translational Analysis from four SOLTI Clinical Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-07.

Abstract Background Pre-clinical evidence and retrospective studies suggest that PAM50 HER2-Enriched (HER2-E), HR+/HER2- tumors have estrogen receptor (ER) independence and poor prognosis but seem to have androgen receptor (AR)-addiction. Enzalutamide (ENZ) is a potent inhibitor of AR signaling. We hypothesized that ENZ may induce a significant proliferative arrest in PAM50 HER2-E, HR+/HER2-negative advanced breast cancer (ABC), leading to clinical benefit in this poor prognosis population. Methods Eligible patients (pts), males or pre/post-menopausal women with advanced HR+/HER2- ABC resistant to endocrine therapy, received ENZ 160 mg/day until disease progression. Pts were assigned to different cohorts according to PAM50 intrinsic subtypes identified in the pre-treatment tumor biopsy: Cohort A included pts with HER2-E and Cohort B pts with Luminal A/B tumors. Centralized molecular assessment of pre-treatment and C1D15 tumor biopsies were required for the primary endpoint evaluation. After C1D15 biopsy, exemestane 50mg QD could be added to ENZ at physician’s discretion. Tumor assessments were performed every 8 weeks. Primary efficacy endpoint was the relative change in the PAM50 11-gene proliferation-related signature in Cohort A. Secondary objectives included anti-proliferative effect of ENZ in Cohort B, overall response rate (ORR), Clinical benefit rate (CBR; partial response [PR] + stable disease ≥ 24 weeks) progression-free survival (PFS), and safety. Results From June 2020 to October 2022, 47 tumors were screened, and 6 PAM50 HER2-E tumors were identified (13%). A total of 34 pts were enrolled: 6 pts in Cohort A and 28 pts in Cohort B. Among them, 4 pts from Cohort A received ENZ plus exemestane and 23 pts in Cohort B. Mean age was 59 (range 39-76), 89% of pts were postmenopausal, 74% had liver disease, and 59% received (neo)adjuvant treatment. The median number of lines for ABC was 4 (1-8). Mean Ki67 (central assessment) in Cohort A was 37% (5%-70%), while in Cohort B it was 30% (3%-90%). Mean central AR in Cohort A was 66% (30-100), while in Cohort B it was 55% (1-100). The mean suppression of PAM50 11-gene proliferation-signature after 2 weeks of treatment with ENZ was 3.7% (p=0.848) in Cohort A and 1.2% (p=0.909) in Cohort B. The median change in Ki67 levels in Cohort A was -0.43% (p=0.812), while in Cohort B it was +3.86% (p=0.081). No statistically significant differentially expressed genes or changes in intrinsic subtypes were observed. Overall, the median PFS was 1.8 months (95% CI 1.6-1.8). In Cohort A, median PFS was 1.6 months (95% CI 1.0-1.9), and in Cohort B, it was 1.8 months (95% CI 1.6-1.8). CBR was 0% and 11% (n=3, 95% CI 2.8-25.9%) in Cohorts A and B, respectively. A PR with 16 months duration in cohort B was observed in a patient with an AR-mutated tumor (AR c. 689C >T). Regarding safety, grade 1-2 and 3-4 toxicities occurred in 94.1% and 35.3% of patients, respectively. ENZ dose reduction and discontinuation occurred in 2 (5.9%) and 3 (8.8%) pts, respectively. The most common toxicities related to ENZ were nausea (n=8, 24%), decreased appetite (n=8, 24%), AST increase (n=6, 18%) and vomiting (n=6, 18%). Conclusions The hypothesis that ENZ could induce proliferation arrest in HR+/HER2-, PAM50 HER2-E tumors was not confirmed, and ARIANNA was prematurely closed due to the lack of efficacy. Additional research is needed to explore if ENZ may benefit specific populations of pts with breast cancer (e.g. AR-mut tumors) and whether alternative AR modulators are more effective in blocking AR signaling in HR+/HER2-, PAM50 HER2-E tumors Citation Format: Mafalda Oliveira, Tomás Pascual, Sonia Pernas, Mireia Margelí, Salvador Blanch, Barbara Adamo, Francisco Javier Salvador Bofill, Xavier Gonzalez-Farré, Samyukta Chillara, Patricia Galván, Esther Sanfeliu, Paula Blasco, Valeria Sirenko, Alejandra Espinosa, Charles M Perou, Aleix Prat, Luis Manso. Targeting PAM50 HER2-Enriched intrinsic subtype with enzalutamide in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer: results of the SOLTI-1502 ARIANNA trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-06.

Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [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 OT3-11-02.

Introduction Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy compared to standard of care endocrine treatment, with greater relative benefit in ESR1-mutated tumors, and manageable safety profile in pretreated patients with metastatic breast cancer (BC) (Bidard F.C., JCO 2022). SOLTI ELIPSE trial (NCT04797728) is a prospective, multicenter, window of opportunity trial designed to assess whether a short-course of preoperative elacestrant may suppress tumor proliferation in postmenopausal women with estrogen receptor positive (ER+)/HER2-negative early BC (Vidal M., SABCS 2021). Here, we present the results of the primary efficacy and safety study analysis. Methods Eligible patients with operable, untreated ER+/HER2-negative BC that were T1c (≥1.5 cm)-T3 by ultrasound, clinically or radiologically N0 and had a locally assessed Ki67 ≥10%, received elacestrant 400 mg once a day continuously for a total of 4 weeks. At the study treatment completion, patients were treated according to local practice. Centralized assessment of post-treatment (D28) Ki67 from surgical specimen or tumor biopsy was required for the primary endpoint evaluation. Primary efficacy endpoint was complete cell cycle arrest (CCCA), defined as Ki67≤2.7%, at D28. Ki67 geometric relative change, variation in tumor infiltrating lymphocytes (TILs), switch in PAM50 subtypes and differential expression of 192 genes from baseline (D1) to D28 was also explored. Adverse events (AEs) were graded according to CTCAE v5.0. Results Between April 2021 and February 2022, 24 patients were enrolled and 22 were evaluable for the primary endpoint. Baseline characteristics were: mean age 69 years (range 50-81); ductal histology 74%; T1c 61%; T2 39%; grade 1-2 83%; median local Ki67 20% (10-70). Baseline PAM50 subtypes distribution was: Luminal A (n=12), Luminal B (n=8), Basal-like (n=1), Normal-like (n=1). At D28, CCCA was achieved in the 27% (n=6) of the patients. Fourteen patients (64%) had D28 Ki67 ≤10%. Paired centralized Ki67 was available in 19 patients. A statistically significant 41% (95% CI, -24 to -58) Ki67 relative reduction (rr) from D1 was observed (p=0.007). CCCA rate was 31% and 17% in patients with D1 Ki67 < 20% (n=13) and D1 Ki67 ≥20% (n=6), respectively. Ki67 varied consistently in both Ki67 < 20% (rr=-38%; 95% CI, -16 to -60) and Ki67 ≥20% (rr=-46%; 95% CI, -20 to -72) groups. Overall, elacestrant was associated with a shift towards a more endocrine sensitive and less proliferative phenotype based on PAM50 gene signatures. CCCA occurred in 45% of Luminal A tumors, whereas no CCCA was observed among Luminal B tumors. Levels of TILs were significantly higher at D28 (mean difference, +3.73; p=0.004). Elacestrant induced high expression of immune-response genes including IGJ, GZMB, CD4, CD8a and suppressed proliferation (e.g., UBE2T, MYBL2, BIRC5, MK67) and estrogen-signaling (e.g., ESR1, PGR, CCND1, BRCA2) genes (false discovery rate 5%). These changes in gene expression were observed both in tumors with D28 Ki67≤2.7% and in those with D28 Ki67 >10%. Overall, 87% of the patients reported any grade AEs. Treatment-related AE occurred in 1 patient (grade 3 cutaneous rash) and led to treatment discontinuation. Most frequently reported AEs (all grade 1) were hot flush (n=6), dyspepsia (n=2), anemia (n=2) and constipation (n=2). No serious AEs were reported. Conclusions In untreated ER+/HER2-negative early BC a short-course preoperative treatment with elacestrant was associated with relevant biological and molecular response and with manageable safety profile. Globally, these findings support further exploration of this highly potent, novel oral SERD in early BC. Citation Format: Maria Vidal, Tomás Pascual, Claudette Falato, Rodrigo Sanchez-Bayona, Montserrat Muñoz, Isaac Cerbrecos, Xavier Gonzalez-Farré, Tomás Cortadellas, Mireia Margelí, Miguel Angel Luna, Christian Siso, Kepa Amillano, Patricia Galván, Fernando Salvador, Alejandra Espinosa, Laia Paré, Esther Sanfeliu, Aleix Prat, Meritxell Bellet Ezquerra. PD13-01 Elacestrant in postmenopausal women with estrogen receptor positive and HER2-negative early breast cancer: primary efficacy and safety analysis of the preoperative, window of opportunity SOLTI-1905-ELIPSE trial [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 PD13-01.

The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is »60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. SOLTI Cancer Research Group. AstraZeneca.