Ceralasertib (cerala) + olaparib (ola) in patients (pts) with homologous recombination repair (HRR)-deficient platinum-sensitive relapsed ovarian cancer (OC) after progression on prior PARP inhibitor (PARPi) treatment (tx).
Year: 2025
Type: conference-abstract
Abstract: 5542 Background: Combining an ATR inhibitor (ATRi) and a PARPi may overcome acquired PARPi resistance based on preclinical and clinical data. We report a Phase 1 study (NCT02264678) of cerala (ATRi) + ola (PARPi) in pts with HRR-deficient OC who had progressed on prior PARPi tx. Methods: Pts had histologically confirmed high-grade serous/endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, with deleterious or suspected deleterious BRCA or HRR mutations ( BRCA m ; HRRm: RAD51C/D m , PALB2 m) or HRR-deficiency (HRD+). Pts received oral cerala 80 mg (d 1–14 every 28 d) + ola 150 mg (throughout) twice daily without/with (Cohort [Co] 1/2) intervening platinum-based tx after initial response and subsequent progression on prior PARPi tx. Primary endpoints were safety/tolerability; ORR per RECIST v1.1 and PFS were secondary endpoints. Emergence of PARPi resistance mechanisms was analyzed in archival/pre-study tx tissue samples. Results: 32 pts were treated, 30 in Co1 (7 ongoing tx at data cutoff: Mar 5, 2024) and 2 in Co2 (cohort closed early). Median age was 63.0 yrs; 68.8% (22/32) had BRCA m/HRRm and 31.3% (10/32) HRD+/non- BRCA m by local assessment. All pts had adverse events (AEs); 40.6% had grade ≥3 AEs (most common were anemia and platelet count reduced, each 21.9%); 6.3% discontinued tx due to AEs. Table shows efficacy in Co1. 24 pts had post-PARPi biopsies evaluable for genomics analysis: 3 (12.5%) had BRCA reversions (rev; 13 pts were BRCA m); 3 (12.5%) had loss of function alterations in DNA damage response (DDR) rewiring genes. Of 16 pts with post-PARPi biopsies evaluable for RAD51 foci, 81.3% (13) had RAD51 high status suggesting HRR functional proficiency as a prevalent PARPi resistance mechanism; of these 13, 61.5% (8; 80% CI, 40.2–79.9) responded to cerala + ola, while no responses occurred in 3 RAD51 low pts (80% CI, 0.0–53.6). Responders included patients with BRCA rev or TP53BP1 m, indicating cerala + ola activity in pts with BRCA rev and alterations in DDR rewiring genes. Other PARPi resistance mechanisms were rare. Conclusions: In this setting of high unmet need, cerala + ola had acceptable safety, a low discontinuation rate, and clinical activity in both BRCA m/HRRm and HRD+/non- BRCA m pts after progression on a prior PARPi. Exploratory analyses highlighted emerging PARPi resistance mechanisms; ongoing assessments of PARPi resistance to inform pt selection and novel combination strategies in post-PARPi settings will be presented. Clinical trial information: NCT02264678 . BRCA m/HRRm n=20 HRD+/non- BRCA m n=10 Total N=30 ORR, % (80% CI) 45 (29.3–61.5) 30 (11.6–55.2) 40 (27.7–53.3) Best response, n (%) Complete 2 (10) 1 (10) 3 (10) Partial 7 (35) 2 (20) 9 (30) Stable 8 (40) 4 (40) 12 (40) PFS Events, n 10 8 18 Median, months (80% CI) 7.5 (5.3–not calculable) 4.5 (1.8–5.3) 5.5 (4.7–7.5)
Source: Journal of Clinical Oncology
Authors: Rene Lynnette Roux, Sophie Postel-Vinay, Mario Campone, Antoine Italiano, Claire Frances Friedman, Myong Cheol Lim, Rowan Miller, Geoffrey Ira Shapiro, Matthew G. Krebs, Graeme Parr, Conor Norris, Daniel Slade, Natalia Lukashchuk, Jyoti Nehra, Olga Murina, Edit Eva Lukacs, Isabelle Laure Ray-Coquard
Institutions: Churchill Hospital, Inserm, Institut Gustave Roussy, Institut Bergonié, Memorial Sloan Kettering Cancer Center, National Cancer Center, St Bartholomew's Hospital, University College London, Dana-Farber Cancer Institute, Manchester Academic Health Science Centre, University of Manchester, The Christie NHS Foundation Trust, AstraZeneca (United Kingdom), AstraZeneca (United States), Centre Léon Bérard
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4410812240