AstraZeneca, Cambridge, United Kingdom
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
Background: O is a PARP inhibitor approved in a number of tumor types and for use in pts with germline (g) mutations in BRCA (BRCAm) 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 gBRCAm. 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 BRCA1/2 (BRCAm; 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 BRCAm (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 BRCAm pts were seen in all subgroups (zygosity, HRD, or g/s origin of mutation), including sBRCAm (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 BRCAm/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 gBRCAm and sBRCAm. Beyond BRCAm, 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.
Strata | Subgroup | O | O+C |
---|---|---|---|
BRCAm | Predicted sBRCAm | 3/4 (75) | 2/4 (50) |
Predicted gBRCAm | 9/16 (56) | 8/18 (44) | |
Unknown | 7/23 (30) | 10/18 (56) | |
HRRm | BARD1m | 2/3 (67) | 0/1 (0) |
RAD51C/Dm | 1/3 (33) | 2/2 (100) | |
ATMm | 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) |
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