| Title: |
PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers |
| Authors: |
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 |
| Publisher Information: |
SPRINGERNATURE |
| Publication Year: |
2024 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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). |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0007-0920 |
| Relation: |
https://hdl.handle.net/11343/349647 |
| Availability: |
https://hdl.handle.net/11343/349647 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.D33111B3 |
| Database: |
BASE |