Olaparib (O) + ceralasertib (C) in patients (pts) with metastatic triple-negative breast cancer (mTNBC): Translational analysis of the VIOLETTE trial.

person Natalia Lukashchuk AstraZeneca, Cambridge, United Kingdom info_outline Natalia Lukashchuk, Kevin Punie, Zbigniew Nowecki, Seock-Ah Im, Anne C. Armstrong, William Jacot, Jee Hyun Kim, Marc A. Webster, Judith Balmaña, Suzette Delaloge, Ed Casson, Bienvenu Loembe, Emma Dean, Joshua Armenia, Andrew NJ Tutt

Authors person Natalia Lukashchuk AstraZeneca, Cambridge, United Kingdom info_outline Natalia Lukashchuk, Kevin Punie, Zbigniew Nowecki, Seock-Ah Im, Anne C. Armstrong, William Jacot, Jee Hyun Kim, Marc A. Webster, Judith Balmaña, Suzette Delaloge, Ed Casson, Bienvenu Loembe, Emma Dean, Joshua Armenia, Andrew NJ Tutt Organizations AstraZeneca, Cambridge, United Kingdom, University Hospitals Leuven, Leuven, Belgium, The Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland, Seoul National University College of Medicine, Seoul National University Hospital, and Cancer Research Institute, Seoul, South Korea, Christie Hospital NHS Foundation Trust, Manchester, United Kingdom, Institut du Cancer de Montpellier, Montpellier, France, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea, Tom Baker Cancer Center, Calgary, AB, Canada, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Gustave Roussy, Villejuif, France, AstraZeneca, Oss, Netherlands, The Institute of Cancer Research, London, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company AstraZeneca Background: O is a PARP inhibitor approved in a number of tumor types and for use in pts with germline (g) mutations in BRCA ( BRCA m) HER2-negative metastatic breast cancer. C is an inhibitor of DDR kinase ATR. Analysis of VIOLETTE (NCT03330847) in pts with mTNBC showed no improvement in PFS with a combination of C and O vs. O, whether in the context of pathogenic BRCAm, non-BRCA HRR pathway mutations (HRRm), or homologous recombination repair (HRR) wildtype (HRRwt) tumors. We report an exploratory translational analysis of predictive genomic biomarkers of response to O ± C beyond g BRCA m. Methods: Pts received O (300 mg twice daily) ± C (160 mg daily; days 1–7; 28-day cycles) as a second- or third-line treatment option. Pts were prospectively stratified into molecular strata based on pathogenic/likely pathogenic alterations in BRCA 1/2 ( BRCA m; n=83) or in ≥1 of 13 selected non- BRCA HRR genes (HRRm; n=40) or HRRwt (n=103) using FoundationOneCDx (F1CDx) sequencing assay of archival tumor sample. Advanced genomic analysis included genome-wide loss of heterozygosity (a marker of HRR deficiency [HRD] with a 16% cut-off to define HRD+ [≥16%] vs HRD− [<16%]), zygosity, and predicted g/somatic (s) status of BRCA and HRR alterations based on a validated computational FMI algorithm. Efficacy was evaluated by blinded independent central review of PFS, RECIST response, and best percentage change from baseline in target lesion size. Results: Out of evaluable pts for origin of BRCA m (n=42), 81% (n=34) were of germline, and 19% (n=8) were of somatic origin. Of pts evaluable for zygosity (n=48), most BRCA alterations were biallelic (90%; n=43), and of pts evaluable for HRD status (n=47), most were HRD+ (94%; n=44). Of HRRwt pts evaluable for HRD status (n=79), 57% were HRD+ (n=45). Responses by biomarker are shown. Responses in BRCA m pts were seen in all subgroups (zygosity, HRD, or g/s origin of mutation), including s BRCA m (ORR: n=3/4 on O; n=2/4 on O+C). Responses were also seen in patients with heterozygous BRCA alteration (n=3/5) by genomic result and in BRCA m/HRD− pts (n=3/3) across both arms. Pts with select HRR genes ( BARD1 , RAD51C/D, ATM, CDK12 ) also achieved responses on O or O+C. Conclusions: Responses to O were seen in pts with both g BRCA m and s BRCA m. Beyond BRCA m, the efficacy of O was observed in pts with alterations in select HRR genes, such as BARD1 or RAD51C/D ; further clinical investigation is required. Small sample size and HRD analysis performed on archival tumor samples should be considered limitations. Clinical trial information: NCT03330847. Overall response rate in selected biomarker subsets; n/N (%). Strata Subgroup O O+C BRCA m Predicted s BRCA m 3/4 (75) 2/4 (50) Predicted g BRCA m 9/16 (56) 8/18 (44) Unknown 7/23 (30) 10/18 (56) HRRm BARD1 m 2/3 (67) 0/1 (0) RAD51 C/ D m 1/3 (33) 2/2 (100) ATM m 0/3 (0) 1/4 (25) CDK12 (co-occurring PPP2R2A ) 0/1 (0) 1/3 (33) HRRwt HRD+ 2/22 (9) 4/23 (17) HRD− 0/17 (0) 1/17 (6)