413P - Characteristics of patients (pts) with previously treated, oestrogen receptor-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) who had rapid progression (RP) in acelERA BC

Background

The phase II acelERA BC study (NCT04576455) compared the oral, selective ER antagonist and degrader (SERD) giredestrant (G) with physician’s choice of endocrine therapy (PCET) in previously treated ER+, HER2– aBC. G was not superior to PCET for progression-free survival (PFS) despite a numerical improvement, which was more pronounced in pts with ESR1 mutations (m). RP (PFS <3 months) has been noted in pts with late-line aBC receiving ET, including oral SERDs. We present exploratory biomarker analyses of circulating tumour (ct)DNA dynamics and characteristics of pts with RP.

Methods

Baseline and Cycle 2, Day 1 ctDNA was evaluated by FoundationOne Liquid CDx. Gene expression was profiled by RNAseq on tumour tissue representing the post-first-line setting (>30 days after aBC diagnosis).

Results

As of 15/07/22, 87/293 pts (30%) with evaluable PFS (10 censored within the first 3 months) had RP. RP did not differ by arm: G 42/145 (29%); PCET 45/148 (30%). Pts with RP were more likely to have received a prior CDK4/6 inhibitor (i; 61% vs. 33%; p < 0.01). In pts with ESR1m, 35/88 (40%) had RP vs. 30/137 (22%) in pts without. Comparing RP vs. non-RP in pts with ESR1m: G2M checkpoint, E2F target and ER gene expression signatures were among those decreased; the proportion of Luminal A PAM50 subtype was increased; and baseline ctDNA levels were significantly higher for pts with RP (p < 0.01), with enrichment of DNMT3A, PIK3CA and RB1 mutations vs. non-RP. Among pts with ESR1m regardless of RP status, those who were CDK4/6i-naive showed meaningful increases in gene pathways associated with inflammatory processes, including IFNα (p < 0.01), IFNγ (p < 0.01) and IL6 (p = 0.03) vs. those with prior CDK4/6i. PFS was improved in pts with undetectable ESR1m levels on-treatment, compared with those whose levels increased (p = 0.03).

Conclusions

Data suggest that RP occurs regardless of ESR1m and is associated with prior CDK4/6i treatment and higher tumour burden, as measured by ctDNA levels. In pts with ESR1m, distinct signalling and mutational profiles were observed, dependent on RP status and prior CDK4/6i. Additional observations will inform ongoing pt selection and drug combination research.

Clinical trial identification

NCT04576455; 6 October 2020.

Editorial acknowledgement

Research support for third-party writing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

M. Martin Jimenez: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, Amgen, Roche/Genentech, Novartis, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Lilly/ImClone, Genentech/Roche, Pierre Fabre; Financial Interests, Institutional, Other, Research funding: Novartis, Roche, Puma. S. Hilz: Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. A. Collier, A. Chibly, P.D. Pérez-Moreno: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. J. Sohn: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Other, Research funding: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, MSD, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi. A. Bardia: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Advisory Role: Novartis, Genentech, Inc./F. Hoffmann-La Roche Ltd, Pfizer, BioTheranostics, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Puma Biotechnology, Daiichi Sankyo/AstraZeneca, Eli Lilly, and Mersana; Financial Interests, Institutional, Other, Research funding: Genentech, Inc., Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Eli Lilly. E. Lim: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Advisory Role: Lilly, Novartis, Pfizer, Gilead, AstraZeneca, Merck Sharp & Dohme, F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Other, Research funding: Novartis, F. Hoffmann-La Roche Ltd/Genentech, Inc.; Financial Interests, Personal, Royalties, Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737: Walter & Eliza Hall Institute of Medical Research . M. Chavez Mac Gregor: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment: MD Anderson Physician’s Network; Financial Interests, Personal, Advisory Role: F. Hoffmann-La Roche Ltd/Genentech, Inc., AstraZeneca, Novartis, Pfizer, Eli Lilly, Exact Sciences, and AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Other, Travel/accommodation/expenses: Pfizer, AstraZeneca, and Exact Sciences; Financial Interests, Personal, Expert Testimony: Abbott Laboratories and Pfizer; Financial Interests, Institutional, Other, Research funding: Novartis and Pfizer; Non-Financial Interests, Personal, Member of Board of Directors, Volunteer member: Legacy Healthcare Services and The Hope Foundation. J. Martinalbo: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. H.M. Moore: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment, Spouse (Pfizer, Inc.): Genentech, Inc., Pfizer, Inc.; Financial Interests, Personal, Stocks/Shares, Spouse (Pfizer, Inc.): F. Hoffmann-La Roche Ltd, Pfizer, Inc..