821TiP Phase I study of ceralasertib (cerala) in combination with AZD5305 in patients (pts) with advanced/metastatic ovarian cancer (OC) previously treated with PARP inhibitors (PARPis)

Combined inhibition of ATR and PARP has been shown to overcome resistance to PARPis in PARPi-resistant cell lines and pt-derived xenograft (PDX) models. Cerala, a selective and potent ATR inhibitor, in combination with olaparib, has demonstrated activity in pts with homologous recombination deficiency-positive, PARPi-resistant OC (CAPRI; NCT03462342). However, in combination with olaparib, the dose and duration of cerala treatment is limited by haematological toxicity. Compared to approved PARPis which target both PARP1 and PARP2, AZD5305 is a highly selective and potent PARP1i which may improve upon the current safety profile of the olaparib and cerala combination. AZD5305 monotherapy was well tolerated in an ongoing phase 1 study of pts with BRCA1/2-, PALB2- or RAD51C/D-mutant advanced breast, prostate, pancreatic or OC (PETRA; NCT04644068); AZD5305 in combination with cerala demonstrated durable tumour regression in BRCA1/2-mutant, PARPi-resistant, breast and OC PDX models. Thus, combining cerala and AZD5305 may provide a better therapeutic index compared with olaparib and cerala. D5330C00004 (NCT02264678) is a modular, phase 1, open-label trial assessing cerala in combination with anti-cancer agents in pts with advanced solid malignancies. Module 5 investigates cerala in combination with AZD5305 in pts with recurrent platinum-sensitive, high-grade, epithelial ovarian, fallopian tube or primary peritoneal cancer (including serous or endometrioid histology), in dose escalation (Part A) and expansion (Part B) cohorts. Key inclusion criteria are age ≥18 years and prior PARPi treatment. Pts in Part B must have a known or suspected BRCA, RAD51C/D or PALB2 mutation. Primary objectives are safety and tolerability of cerala in combination with AZD5305 including the number of adverse events (AEs) and serious AEs, in order to select a recommended phase 2 dose (Part A). Secondary objectives include assessment of antitumour activity, pharmacokinetics and pharmacodynamic biomarkers. Recruitment started in April 2023 and sites across North America, Europe and Asia Pacific will enrol up to 150 pts in total. NCT02264678; 15 October 2014. Medical writing support for this abstract, under the direction of the authors, was provided by Harriet Gallegos of Ashfield MedComms, an Inizio company, and was funded by AstraZeneca. AstraZeneca. AstraZeneca.