PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers

Kristeleit, R; Leary, A; Oaknin, A; Redondo, A; George, A; Chui, S; Seiller, A; Liste-Hermoso, M; Willis, J; Shemesh, CS; Xiao, J; Lin, KK; Molinero, L; Guan, Y; Ray-Coquard, I; Mileshkin, L

Author(s): Kristeleit, R; Leary, A; Oaknin, A; Redondo, A; George, A; Chui, S; Seiller, A; Liste-Hermoso, M; Willis, J; Shemesh, CS; Xiao, J; Lin, KK; Molinero, L; Guan, Y; Ray-Coquard, I; Mileshkin, L;
Details: Publication Year 2024-09,Volume 131,Issue #5,Page 820-831
Journal Title: British Journal of Cancer
Publication Type: Research article
Abstract: BACKGROUND: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). METHODS: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. RESULTS: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. CONCLUSIONS: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03101280).
Publisher: Springer Nature
Keywords: Humans; Female; *Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage/adverse; effects/therapeutic use; *Triple Negative Breast Neoplasms/drug therapy/pathology; *Antibodies, Monoclonal, Humanized/administration & dosage/adverse; effects/therapeutic use; *Indoles/administration & dosage/adverse effects/therapeutic use; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects; Middle Aged; Aged; Adult; Ovarian Neoplasms/drug therapy/pathology/genetics; B7-H1 Antigen; BRCA1 Protein/genetics
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41416-024-02776-7
Open Access at Publisher's Site: https://doi.org/10.1038/s41416-024-02776-7
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-12 06:49:07

Last Modified: 2024-09-12 06:49:36