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)

Abstract

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. Method(s): 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 (BRCAm; HRRm: RAD51C/Dm, PALB2m) 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. Result(s): 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 BRCAm/HRRm and 31.3% (10/32) HRD+/non-BRCAm 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 BRCAm); 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 TP53BP1m, indicating cerala + ola activity in pts with BRCA rev and alterations in DDRrewiring genes. Other PARPi resistance mechanisms were rare. Conclusion(s): In this setting of high unmet need, cerala + ola had acceptable safety, a low discontinuation rate, and clinical activity in both BRCAm/HRRm and HRD+/non-BRCAm 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.