266P - Association of RAD51 and efficacy outcomes in patients with HER2-negative breast cancer (BC) and homologous recombination deficiency (HRD): Post-hoc analysis of the GeparOla trial

Background

The randomized GeparOla trial (NCT02789332) evaluated olaparib vs carboplatin in patients with early HER2- BC and HRD assessed by Myriad myChoice or g/s BRCA mutation. The primary analysis reported comparable pCR rates in both study arms. Current HRD genomic tests show limitations for patient selection. Here, we evaluated the prognostic and predictive capacity of a functional HRD assay using the RAD51 test.

Methods

This is a post-hoc, blinded, biomarker analysis from the GeparOla trial. Patients received paclitaxel (P) plus olaparib or P plus carboplatin, both followed by epirubicin/cyclophosphamide. RAD51 foci on FFPE tumors were quantified by an immunofluorescence assay (pre-defined cut-off of 10%). The primary objective was to evaluate the association between RAD51 and pCR. Uni/multivariable logistic models were used to estimate odds-ratios (OR) with 95% confidence interval (95% CI).

Results

Of 97 samples available from 107 randomized patients, 90 (93%) were evaluable for RAD51-testing. Most patients were N0 (76%), triple-negative (77%), had a Ki67>20% (93%), sTILs>10% (51%) and had low RAD51 tumors (80%). The pCR rate in patients with RAD51 low tumors was 67% (48/72) while it decreased to 22% (4/18) in RAD51 high (OR=0.14, p=0.001). In patients treated with olaparib, those with RAD51 low tumors (n=45) had a pCR rate of 69%, compared to 27% in RAD51 high (n=15). Similar trends were observed in carboplatin-treated patients, with pCR rates of 63% (n=27) vs 0% (n=3) favouring RAD51-low tumours. RAD51 score remained statistically associated with pCR after adjusting by clinicopathological factors (OR=0.11, 95% CI 0.03-0.43, p=0.002). No differences were observed between RAD51 groups and disease-free survival (RAD51 high vs low, hazard ratio=0.85, 95% CI 0.25-2.97).

Conclusions

In a pre-selected HRD population, RAD51 low tumors had a significantly higher pCR rate than RAD51 high tumors under platinum or PARPi-based therapies. This finding underscores the potential of RAD51 to tailor treatment strategies and to improve patient selection for future clinical trials.

Clinical trial identification

NCT02789332.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The GeparOla study was financially supported by AstraZeneca. The RAD51 test received funding from ERA-NET Cofund [ERAPERMED2019-215].

Disclosure

G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. N. Filmann: Financial Interests, Institutional, Full or part-time Employment, Natalie Filmann declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending.: GBG Forschungs GmbH. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, Astrazeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis, Medac, Menarini, Veracyte; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead, Mylan; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Local PI: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. J. Balmaña: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Educational programs: AstraZeneca -MSD; Financial Interests, Institutional, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Local PI: MedSir. F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad, Seagen; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca, Stemline Menarini; Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Local PI: Roche, Novartis, Eisai, MSD, Vaccibody, GSK; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Roche, Gilead/Immunomedics, German Breast Group, AGO Research GmbH; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. V. Mueller: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Lilly, Medscape, Gilead, Pierre Fabre, iMED Institut; Financial Interests, Personal, Advisory Board: Roche, Pierre Fabre, PINK, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Seagen, Gilead, Stemline; Financial Interests, Institutional, Local PI: Novartis, Roche, Seagen, Genentech, AstraZeneca; Non-Financial Interests, Leadership Role: AGO German Breast Cancer Guideline Group. C. Schem: Financial Interests, Personal, Advisory Board: Roche, Novartis, Lilly, AstraZeneca, Daichi Sanyo, Exact Sciences, Celgene, MSD, Reagan; Financial Interests, Institutional, Local PI: AstraZeneca, Roche, Gilead. V. Nekljudova: Financial Interests, Personal, Full or part-time Employment: GBG Forschungs GmbH; Financial Interests, Institutional, Other, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0: GBG; Financial Interests, Institutional, Funding: Abbvie, Amgen, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Molecular health, Novartis, Pfizer, Roche; Non-Financial Interests, Other, non-financial: Daiichi Sankyo; Non-Financial Interests, Other, non-financial, institutional: Gilead, Pfizer, Roche, Novartis; Non-Financial Interests, Other, non-financial/institutional: Seagen. A. Llop-Guevara: Financial Interests, Ownership Interest: WO2019122411A1; Financial Interests, Full or part-time Employment: Astrazeneca. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly, Diaceutics, VmScope digital pathology software; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. S. Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, GSK, Lilly, Pierre Fabre, Roche, Seagen, Abbvie, Sanofi, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pfizer, Roche, Gilead, Seagen, Stemline-Menarini; Financial Interests, Institutional, Advisory Board: Pfizer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Advisory Board, Ki67 Quantifier: VMscope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis, Immunomedics/Gilead, Pfizer, Roche, Daiichi Sankyo; Financial Interests, Institutional, Funding: AbbVie, Molecular Health, Greenwich Life Sciences; Financial Interests, Personal, Other, PIPenelope/Padma: Pfizer; Financial Interests, Personal, Other, SC PALOMA3: Pfizer; Financial Interests, Personal, Other, SC SOLAR1: Novartis; Financial Interests, Personal, Other, SC ASCENT: Immunomedics/Gilead; Financial Interests, Personal, Other, SC HERCLIMB: Seagen; Financial Interests, Personal, Other, SC Katherine: Roche; Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests, Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, Member, German Cancer Society: DKG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Other, EP14153692.0No financial interest, Institutional: Patent; Other, EP21152186.9No financial interest, institutional: Patent; Other, EP19808852.8 No financial interest, Institutional: Patent. V. Serra: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Other, WO2019122411A1: Methods based on the detection of rad51 foci in tumor cells: TBD; Financial Interests, Institutional, Research Grant, Testing various novel targeted agents in patient-derived tumour models: AstraZeneca. All other authors have declared no conflicts of interest.